INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNOVATION (IJRSI)

ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |Volume XII Issue X October 2025

Hepatoprotective and Antihyperglycemic Effects of Sea Grapes

(Caulerpa spp.) as a Potential Therapeutic Approach for NAFLD and

NASH

Yasmin Azzahra Arifin¹, Annette d’Arqom^2*

¹Faculty of Medicine, Universitas Airlangga, Surabaya, East Java, 60131, Indonesia.

²Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine, Universitas Airlangga,

Surabaya, East Java, 60131, Indonesia.

DOI: https://dx.doi.org/10.51244/IJRSI.2025.1210000319

Received: 02 October 2025; Accepted: 08 October 2025; Published: 21 November 2025

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), are

increasingly prevalent metabolic liver disorders characterized by hepatic lipid accumulation, oxidative stress,

inflammation, and insulin resistance. Despite their global burden, effective pharmacological treatments remain

limited, which highlights the need for safe and multi-targeted natural alternatives. This literature review

summarizes current evidence from in vitro, in vivo, and early clinical studies investigating the hepatoprotective

and antihyperglycemic properties of Caulerpa spp., including C. lentillifera, C. racemosa, C. taxifolia, and C.

prolifera. The review focuses on research published between 2015 and 2025 related to Caulerpa bioactivity,

liver protection, glucose regulation, oxidative stress, lipid metabolism, and gut microbiota modulation. Across

the reviewed studies, Caulerpa-derived bioactive compounds such as polysaccharides, carotenoids, peptides,

and polyphenols consistently demonstrated hepatoprotective and metabolic benefits. Supplementation improved

antioxidant enzyme activities, including superoxide dismutase, catalase, and glutathione, while reducing

malondialdehyde levels, thereby protecting hepatocytes from oxidative damage that contributes to NAFLD

progression. Several studies also reported downregulation of lipogenic genes such as SREBF1, FAS, and ACC,

together with activation of SIRT1 and AMPK signalling pathways, which reduced hepatic triglyceride

accumulation. Extracts from C. taxifolia and C. prolifera exhibited strong alpha-amylase and alpha-glucosidase

inhibition, improving glucose regulation. In addition, Caulerpa supplementation was shown to restore intestinal

barrier integrity and modify gut microbiota composition, leading to lower endotoxin levels and reduced hepatic

inflammation. The only available human clinical trial demonstrated a significant reduction in fasting glucose

following C. racemosa supplementation, supporting its potential for clinical application. Overall, the evidence

indicates that Caulerpa species exert multi-pathway hepatoprotective and antihyperglycemic effects. However,

further studies are required to standardize extract preparation, determine optimal dosage, and assess long-term

safety. Caulerpa spp. demonstrates promising preclinical potential. However, further translational research and

rigorous clinical trials are warranted to validate these findings and determine its feasibility as a nutraceutical for

NAFLD, NASH, and metabolic syndrome.

Keywords: Caulerpa spp, Sea grapes, Hepatoprotective, Anti hyperglycemic, Fatty liver disease, Metabolic

syndrome

INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) and its more severe form, non-alcoholic steatohepatitis (NASH), are

major global health problems linked to obesity, insulin resistance, and type 2 diabetes. Affecting nearly one-

third of the world’s population, NAFLD is considered the hepatic manifestation of metabolic syndrome,

characterized by excessive lipid accumulation in hepatocytes independent of alcohol consumption. Persistent

hepatic steatosis can progress to chronic inflammation, fibrosis, and cirrhosis, posing a significant risk for

hepatocellular carcinoma. The underlying mechanisms of NAFLD and NASH involve oxidative stress,

mitochondrial dysfunction, endoplasmic reticulum stress, and dysregulation of lipid and glucose metabolism

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[3][6]. Despite the high prevalence of NAFLD, current pharmacological treatments remain limited. Management

strategies largely depend on diet and lifestyle modification, as no approved first-line drugs are available.

Therefore, natural marine-derived compounds with antioxidant, metabolic, and gut-modulating effects are

attractive alternatives. Caulerpa spp. are unique among green macroalgae due to their high sulfated

polysaccharide and carotenoid content, which have shown strong metabolic regulatory activity in recent

preclinical studies Species such as C. racemosa, C. lentillifera, C. taxifolia, and C. prolifera contain a rich array

of bioactive compounds. Preclinical evidence suggests these compounds hold therapeutic promise. Experimental

studies, using both in vivo animal models and in vitro cell lines, have shown that Caulerpa extracts can modulate

key molecular pathways associated with lipid metabolism and energy balance, such as the SIRT1/AMPK and

mTOR signaling cascades. Furthermore, emerging research highlights mechanisms central to NAFLD/NASH

pathophysiology, including the inhibition of digestive enzymes like α-amylase, the suppression of oxidative

stress, and the modulation of the gut-liver axis through changes in gut microbiota composition [3][5][7][9].

This review therefore aims to synthesize and analyze recent findings on the hepatoprotective and

antihyperglycemic effects of sea grapes (Caulerpa spp.) and relating to NAFLD and NASH treatment. By

integrating biochemical, molecular, and microbiome perspectives, this paper provides a comprehensive

understanding of how Caulerpa-derived compounds contribute to metabolic and hepatic protection, establishing

a foundation for future nutraceutical development and clinical translation.

MATERIAL AND METHOD

Research Strategy

A structured literature search was conducted in Scopus (Elsevier) and PubMed using the keyword phrases “Sea

grapes” OR “Caulerpa” OR “Caulerpa lentillifera” OR “Macroalgae” AND “Liver disease” OR “NAFLD” OR

“NASH” OR “Liver steatosis” OR “Fatty liver disease.” OR "blood glucose" OR "anti diabetic" OR "blood sugar

regulation" The search was performed on 5 November 2025 (Asia/Surabaya) and limited to publications from

2015–2025. The initial query returned 95 for Scopus (Elsevier). Titles and abstracts were screened for relevance

to the hepatoprotective and blood glucose-lowering effects of sea grapes for treating NAFLD and NASH. Only

English-language publications were included. After applying these criteria, 15 studies were retained for full-text

review and included in this narrative literature review. The detailed study selection process, outlining study

identification, screening, eligibility, and inclusion, is summarized in the PRISMA 2020 Flowchart (See Figure

1)

Figure 1 Prisma Flowchart

Identification of studies via databases and registers

Records removed before screening:

Records identified from:

Duplicate records removed (n = 54)

Databases (n = 149)

Records removed for other reasons

Registers (n = 0)

(n = 0)

Records screened

(n = 95)

Records excluded

(n = 80)

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Reports not retrieved

(n = 0)

Reports sought for retrieval

(n = 15)

Reports excluded: 0

Reports assessed for eligibility

(n = 15)

Studies included in review

(n = 15)

Reports of included studies

(n = 15)

Inclusion and Exclusion Criteria

Inclusion criteria: Articles published between 2015–2025, written in English, involving Caulerpa spp. or sea

grapes (including extracts or isolated bioactive compounds), and reporting hepatoprotective and/or

antihyperglycemic effects in NAFLD, NASH, fatty liver disease, liver steatosis, insulin resistance, or

hyperglycemia in in vivo, in vitro, or clinical studies Exclusion criteria: Non-English publications; articles

without liver- or glucose-related outcomes; studies on algae not belonging to Caulerpa spp., reviews, editorials,

or conference abstracts without primary data, studies focusing only on chemical composition without biological

activity, and studies unrelated to metabolic or liver disease models.

Quality and Risk-of-Bias Assessment

The methodological quality of the included studies was independently assessed by reviewers. The risk-of-bias

for in vivo (animal) studies was conducted using criteria from the SYRCLE (Systematic Review Centre for

Laboratory animal Experimentation) checklist. For the single clinical trial, the Cochrane Risk-of-Bias 2 (RoB 2)

tool was used. In vitro studies were assessed using the SciRAP (Science in Risk Assessment and Policy) method,

which evaluates both reporting quality and methodological quality based on predefined criteria such as clarity

of test system description, exposure characterization (e.g., concentrations), adequacy of controls, and replication.

Any disagreements in assessment were resolved through discussion or consensus. The results of this risk-of-bias

assessment are summarized and integrated into the synthesis tables (Tables 1-3).

Data Extraction and Synthesis

From the 15 studies, we extracted aggregate data on study design (e.g., in vivo animal model, in vitro cell culture,

or human clinical trial), sample characteristics (e.g., species, strain, or participant demographics), and

intervention specifics (e.g., Caulerpa species, extract type, dosage, and duration). Key outcome measures were

categorized by hepatoprotective effects (including changes in liver enzymes, hepatic fat accumulation, oxidative

stress markers, and fibrosis) and antidiabetic effects (including fasting blood glucose, enzyme inhibition, insulin

levels, and metabolic regulators like PGC-1). Evidence was synthesized narratively, with harmonization of effect

measures where feasible. No meta-analysis was performed due to the significant heterogeneity observed across

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study models, intervention protocols, and outcome measures. Although a meta-analysis was not performed, the

narrative synthesis includes an evaluation of the overall strength of evidence based on an adapted GRADE

(Grading of Recommendations, Assessment, Development and Evaluations) framework. The strength of

evidence was categorized as 'high', 'moderate', 'low', or 'very low' based on study risk of bias, consistency of

findings, and the precision of the reported preclinical data.

RESULT AND DISCUSSION

Hepatoprotective Effects of Caulerpa spp.

Multiple studies demonstrate Caulerpa spp, possess notable hepatoprotective activities, primarily through

enhancing endogenous antioxidant defenses, reducing hepatic inflammation, and restoring liver enzyme balance.

In a diquat-induced liver injury model, supplementation with Caulerpa lentillifera significantly decreased ALT

levels (from approximately 29 U/mg to 20 U/mg) while increasing SOD activity (from 38 U/mg to 46 U/mg),

indicating an effective reduction of oxidative stress within hepatocytes [1]. Comparable protective outcomes

were observed in ethanol-induced liver injury, where C. lentillifera administration alleviated elevations in AST

and GGT and lowered hepatic inflammation scores. These benefits were accompanied by suppression of TLR4-

mediated inflammatory signaling and recovery of intestinal tight-junction proteins such as occludin and ZO-1

[5]. In high-fat diet (HFD) animal models, sulfated polysaccharides derived from C. racemosa significantly

decreased oxidative stress markers and enhanced the activity of endogenous antioxidant enzymes, further

confirming its hepatoprotective potential [7]. Supplementation with C. lentillifera in animals with metabolic

syndrome similarly improved hepatic SOD activity and reduced lipid accumulation in liver tissue [10]. Since

oxidative stress plays a central role in the development and progression of NAFLD, these consistent findings

suggest that Caulerpa supplementation may prevent early hepatocellular damage and slow the transition to

steatohepatitis.

Antihyperglycemic and Metabolic Effects

The reviewed studies also reveal strong antihyperglycemic effects across different Caulerpa species. A sulfated

galactan isolated from C. taxifolia improved insulin sensitivity, reduced fasting blood glucose, and inhibited α-

amylase activity in diabetic mice [3]. Polyphenolic extracts of C. prolifera demonstrated potent α-glucosidase

and α-amylase inhibition in vitro, with compounds such as vanillin and kaempferol showing strong enzyme-

binding affinity [4]. In vivo studies confirmed glucose-lowering effects, as C. racemosa supplementation

significantly reduced blood glucose levels in obese and high-fat diet animal models [9,12], while C.

lentillifera improved glucose profiles in metabolic syndrome rats [10]. Notably, the only available double-blind,

placebo-controlled human trial demonstrated that 4-week supplementation with C. racemosa significantly

reduced mean fasting blood glucose in obese adults, from a baseline of 113.68 mg/dL to 79.82 mg/dL (p=0.000)

[11].These findings suggest that Caulerpa acts through multiple mechanisms, including enzyme inhibition,

increased insulin sensitivity, and improved hepatic glucose metabolism.

Comparison on Caulerpa spp.

Although hepatoprotective and antidiabetic effects were observed across all species, different Caulerpa types

demonstrated distinct therapeutic strengths. C. lentillifera consistently showed antioxidant and anti-steatosis

activity, preventing hepatic lipid accumulation and reducing oxidative injury in zebrafish, rats, and HepG2 cells

[1,5,6]. C. racemosa produced the strongest antihyperglycemic effects in both preclinical and clinical studies

and significantly improved gut microbiota composition in high-fat diet models [7,9,11]. C. taxifolia and C.

prolifera exhibited potent α-amylase and α-glucosidase inhibition due to high phenolic and polysaccharide

content [3,4]. These differences suggest the possibility of species-specific application, where C. lentillifera may

be more suitable as an antioxidant hepatoprotective agent, while C. racemosa and C. taxifolia may serve as

effective glucose-lowering and metabolic regulators.

Table 1 Summary Of In Vitro Studies on The Metabolic Effects of Caulerpa Spp.

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Study

(Author,

Year)

Caulerpa

Species

Model Cell /

Assay

Key Finding

Mechanism

Risk of Bias

Assessment

Sangpairoj et C. lentillifera

HepG2

↓Lipid accumulation;

↑ SIRT1/AMPK

Low Risk

hepatocytes;

assays: MTT

cytotoxicity,

Oil Red O

al. (2024)

↓Trigliserida

Pathway,

↓Lipogenesis genes

(SREBF1, FAS, ACC)

Potential binding of

major compounds (dl-2-

phenyltryptophane,

benzoic acid) to SIRT1

and AMPK (via

staining,

Triglyceride

assay, qPCR,

Western blot

docking)

Ouahabi S. et

al. (2025)

C. prolifera

Assay α -

mylase & α-

glucosidase

Strong inhibitory activity;

some extracts (ME,

Digestive enzyme

inhibition (slower carb

breakdown & glucose

absorption

Low Risk

AQE) comparable or

superior to acarbose

DPPH & β-

carotene

bleaching

Aqueous/methanolic

extracts show strong

radical scavenging; EA

strongest in lipid

Antioxidant

activity (radical

scavenging & lipid

oxidation inhibition)

peroxidation inhibition

Dissanayake,

I.H et al.

(2022)

C. racemosa

DPPH, FRAP

Moderate–strong

antioxidant activity;

strong correlation with

phenolic & flavonoid

content

Free-radical scavenging

& reducing activity

α-amylase &

α-glucosidase

inhibition;

Anti-glycation

assays

Strong inhibition of α-

amylase (CPE) and α-

glucosidase (EA

fraction); clear dose–

response; notable anti-

glycation effects

Digestive enzyme

inhibition → potential

postprandial glucose

control

Nurkolis et

al. (2023)

C. lentillifera

HepG2

hepatocytes

(lipid

↓Lipid accumulation;

↓TG; ↑SIRT1/AMPK

Lipid-lowering

via SIRT1–AMPK

activation

Moderate

Risk

accumulation

assays)

Table 2 Summary of In Vivo (Animal Model) Studies on The Hepatoprotective And Antidiabetic Effects of

Caulerpa Spp

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Study

(Author,

Year)

Key Findings

Animal

Model

Risk of Bias

Assessment

(Liver &

Glucose)

Caulerpa Species

Dose

Duration

Glucose:

↓ Blood Glucose

↑ glut2 & akt

mRNA (Insulin

signaling)

Zebrafish

(Danio rerio)

(Diquat-

induced

oxidative

damage)

Liver:

20 g/kg &

50 g/kg in

diet

C. lentillifera

Lin X et al.

(2024)

Medium

Risk

↓ Liver MDA

(Oxidative stress)

56 days

(Dried powder)

↑ SOD activity

(Antioxidant)

↓ ALT & AST

(Liver enzymes)

↓ Hepatic TG

↓Histopathological

lesions

Glucose &

Metabolism:

↓ Blood Glucose

↓ α-glucosidase &

α-amylase activity

↓ Lipase activity

22.5

mg/kg &

45 mg/kg

BW

Kurniawan,

R. et al.

C. racemosa

(Carotenoids) & C.

lentillifera (Peptide).

Male Rattus

norvegicus

fed a CFED

Liver & Lipids:

↓ TG, TC, LDL

↑ HDL

4 weeks

Low Risk

(2025)

↓ AST (Liver

enzyme)

↓ TNF-α,

↑ IL-10

Male

C57BL/6J

mice (T2DM

Liu, S. et

al. (2025)

C. taxifolia (Sulfated

Medium

Risk

100, 200,

400

Glucose & Insulin:

↓ Fasting Blood

5 weeks

galactan - SGC)

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model)

mg/kg/day

Glucose

↓ HOMA-IR

(Insulin

Resistance)

↑ Glucose

Tolerance (OGTT)

Liver & Oxidative

Stress:

↓ Liver damage

(vacuolation)

↑ Antioxidants

(SOD, CAT, GSH)

↓ MDA (Oxidative

stress marker)

Glucose:

No glucose data

measured.

Liver & Gut:

↓ Serum AST &

GGT

↓ Liver

inflammation

score ↔ Liver

steatosis, Hepatic

Male Wistar

rats (Chronic

ethanol

5% in

Lin K.Y. et

al. (2023)

C. lentillifera (Dried

liquid diet 12 weeks TC & TG (No

Low Risk

powder)

(8.4 g/L)

change)

exposure)

↓ Circulatory

endotoxin

↓ Hepatic TNF-α

& IL-1β

↓ TLR4 pathway

(Inflammation)

↑ Intestinal

Occludin & ZO-1

↓ F/B ratio;

↑ Akkermansia

Mayulu, N.

et al.

Male Rattus

norvegicus

fed a CFED

65 & 130

mg/kg

BW

Glucose &

6 weeks Metabolism:

C. racemosa (Sulfated

Polysaccharide - SPCr)

Medium

Risk

(2023)

↓ Blood Glucose

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(High dose most

effective)

↓ Serum Lipase &

Amylase Liver &

Lipids: ↔ AST &

ALT (No

significant change)

↓ HMG-CoA

Reductase ↑ SOD

Cardio

Glucose &

Metabolism:

↓ Blood Glucose

↓ Serum Amylase

& Lipase

Male albino

Swiss mice

fed a CFED

65 & 130

mg/kg

BW

Nurkolis et

al. (2023)

C. racemosa (Aqueous

Liver & Lipids:

↓ TG, TC, LDL;

↑ HDL

Medium

Risk

6 weeks

extract - AEC)

↑ Cardio SOD

↓ PRMT-1 &

ADMA

(Cardiometabolic

markers)

Glucose:

↓ Blood Glucose

Liver & Lipids:

Manoppo,

J.I.C. et

al. (2022)

Male Rattus 150 & 450

Medium

Risk

C. lentillifera (Extract)

norvegicus

mg/kg

BW

4 weeks

↓ Total

fed a CFED

Cholesterol ↑

Liver SOD

(Antioxidant)

↑ PGC-1α

(Mitochondrial

biogenesis)

Glucose:

Kuswari

M. et al.

(2021)

Male Wistar 150 & 450

↓ Blood Glucose

(150 mg/kg > 450

mg/kg)

albino rats

mg/kg

BW

C. racemosa (Extract)

4 weeks

High Risk

fed a CFED

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Liver & Lipids: ↓

Total Cholesterol

Glucose & Insulin:

↓ Fasting Blood

Glucose

↑ Serum Insulin

Liver/Kidney

(Hepatoprotective)

:

Male Wistar

albino rats

(Diabetic

Nephropathy:

high fructose

+ STZ)

C. racemosa

↓ Serum TC, TG,

LDL-C

100 & 400

mg/kg

Cao, M. et

al. (2021)

Medium

Risk

8 weeks

(Polysaccharide extract -

PCR)

BW

↓ Renal MDA

(Oxidative stress)

↑ Renal

Antioxidants

(SOD, CAT, GSH-

Px)

↓ Renal Cytokines

(IL-1β, IL-6, TNF-

α)

↓ Renal Fibrosis &

Lesions

Glucose: ↔ Basal

Blood Glucose

(No reduction) ↔

Glucose Tolerance

(No improvement)

Male Wistar

rats fed

High-Carb

High-Fat diet

C. lentillifera

Liver & Lipids:

du Preez, R

et al. (2020

Medium

Risk

5% in diet 8 weeks

(Dried, whole)

↓ Liver Fat

Deposition &

Inflammation ↔

Plasma ALT &

AST (No change)

↓ Total

Cholesterol &

NEFA

Glucose & Insulin:

↓ Fasting Blood

Glucose ↑ Glucose

& Insulin

C57BL/KsJ-

db/db mice

(Genetic

250 & 500

mg/kg

BW

C.lentillifera

Sharma et

al. (2015)

Medium

Risk

6 weeks

(Ethanol extract - CLE)

T2DM)

Tolerance

(OGTT/IPITT) ↓

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HOMA-IR

Liver &

Metabolism: ↑

Hepatic Glycogen

↑ GK activity,

↓ G-6Pase activity

Table 3 Summary of Clinical (Human) Studies on The Metabolic Effects of Caulerpa Spp.

Study

(Author,

Year)

Caulerpa

Species

Study

Design

Participants

(n)

Key Quantitative

Findings

Risk of Bias

Assessment

Dose

Duration

↓ Blood

69 obese

men (BMI

25–30

Glucose: Significantly

lower (p<0.0001)

compared to placebo

RCT,

double-

blind,

1.68

g/day of

sea

grape

extract

or

kg/m²)

Permatasari

et al. (2022)

completed

the study (35

in extract

group, 34 in

placebo

Some

Concerns

C. racemosa placebo-

4 weeks

↑ PGC-

controlled

clinical

trial

1α: Significantly

higher (p=0.000)

compared to placebo

placebo

group)

Caulerpa spp. as a Potential Therapy for NAFLD and NASH

Non-alcoholic fatty liver disease (NAFLD) progresses to non-alcoholic steatohepatitis (NASH) through a series

of interrelated metabolic and inflammatory disturbances. Persistent insulin resistance promotes excessive

delivery of free fatty acids to the liver and stimulates de novo lipogenesis via regulatory factors such as SREBP-

1c, FAS, and ACC, resulting in hepatocellular triglyceride accumulation and lipotoxicity [16][17]. As lipid

burden increases, mitochondrial β-oxidation becomes impaired, generating reactive oxygen species and lipid

peroxidation products such as malondialdehyde. These oxidative insults induce hepatocyte injury and activate

inflammatory cascades, including TLR4–NF-κB signaling, which further amplify cytokine production and

immune cell recruitment [16][19]. Concurrently, gut dysbiosis and disruption of intestinal barrier function

increase endotoxin translocation into portal circulation, promoting hepatic inflammation, stellate-cell activation,

and fibrogenesis through the gut–liver axis [17][18]. Collectively, lipid overload, oxidative stress, inflammation,

and microbiome-mediated hepatic injury constitute the major mechanisms driving progression from simple

steatosis to NASH.

Within this pathogenic framework, evidence from in vitro and in vivo studies demonstrates that species

of Caulerpa exert hepatoprotective and antihyperglycemic effects through multiple biochemical

pathways. Caulerpa lentillifera supplementation has been shown to restore endogenous antioxidant defense

systems. For instance, in a diquat-induced zebrafish model, 50 g/kg supplementation restored the protective

enzyme SOD activity (from ~38 U/mg to ~46 U/mg) while concurrently lowering the liver damage marker ALT

(from ~29 U/mg to ~20 U/mg). In zebrafish and HepG2 hepatocyte models, C. lentillifera downregulated

SREBF1, FAS, and ACC, and activated SIRT1–AMPK signaling, indicating a metabolic shift that reduces

lipogenesis and enhances fatty-acid oxidation [1][6]. These mechanisms directly counteract oxidative injury and

metabolic stress, key pathological drivers of NAFLD progression.

Comparable outcomes have been reported for Caulerpa racemosa. Dietary supplementation and sulfated

polysaccharide fractions significantly reduced triglycerides, LDL cholesterol, and fasting glucose while

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increasing HDL concentrations in cholesterol-fat enriched diet models [7][9]. Mechanistic analysis revealed

modulation of the PRMT-1/DDAH/ADMA and mTOR–SIRT1–AMPK pathways, further supporting its role in

restoring metabolic and endothelial homeostasis [7][9]. These targets overlap with those of established metabolic

therapies, suggesting that Caulerpa may offer pharmacologically relevant benefits derived from natural sources.

A distinct advantage of C. lentillifera is its regulatory effect on the gut–liver axis, a central component in the

transition from NAFLD to NASH. Findings from ethanol-induced liver injury models reported three major

protective mechanisms [5]:

1. Anti-inflammatory regulation: C. lentillifera supplementation suppressed hepatic TLR4 signaling by

downregulating TLR4, MyD88, and TRIF, which reduced the p-NF-κB/NF-κB ratio and lowered pro-

inflammatory cytokines TNF-α and IL-1β.

2. Barrier function: Supplementation reversed the ethanol-induced decline of tight-junction proteins,

strengthening intestinal barrier integrity and significantly decreasing circulating endotoxin.

3. Microbiota modulation: C. lentillifera normalized the Firmicutes-to-Bacteroidetes ratio and increased

beneficial taxa such as Akkermansia, which correlated positively with occludin and ZO-1 expression.

Additional studies involving C.taxifolia and C.prolifera demonstrate complementary antidiabetic and

hepatoprotective effects. Sulfated galactans and phenolic constituents, including vanillin and kaempferol,

inhibited α-amylase and α-glucosidase activity, improved insulin sensitivity, and reduced postprandial glucose

[3][4]. Carotenoid- and peptide-rich fractions of Caulerpa also reduced body weight, hepatic lipid deposition,

and blood glucose levels while enhancing microbiota diversity [2]. These combined antioxidant,

antihyperglycemic, and microbiota-mediated effects align closely with the mechanistic requirements for slowing

NAFLD progression and preventing transition to NASH.

Overall, Caulerpa spp. intervene at multiple critical stages of NAFLD pathophysiology, including metabolic

regulation, oxidative stress reduction, inflammatory suppression, and stabilization of the gut liver axis., the

inhibition of digestive enzymes such as C. racemosa extract demonstrating 81.67% inhibition of α- glucosidase

and 84.07% inhibition of α- amylase, indicates significant antidiabetic potential. Other studies found C.

racemosa's ethyl acetate fraction effectively inhibited alpha-glucosidase with an IC50 value of 153.87 μg/ml,

aligning with the therapeutic actions of standard antidiabetic drugs like acarbose.

Integrative Hepatoprotective Mechanisms of Caulerpa spp. Against NAFLD/NASH

Figure 2 Integrative Hepatoprotective Mechanisms

Given the multi-target biological activities demonstrated by Caulerpa spp. across the reviewed literature, an

integrative mechanistic pathway diagram is essential to improve conceptual clarity and visually synthesize the

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interconnected hepatoprotective and antihyperglycemic mechanisms. Prior figures in the manuscript separately

illustrate oxidative stress reduction, modulation of lipid metabolism, enzyme inhibition, and microbiota

regulation; however, presenting these mechanisms collectively will provide a more cohesive visualization of

how Caulerpa-derived compounds act simultaneously on multiple organ systems. This integrative figure is

particularly relevant for NAFLD/NASH, which itself is a multi-hit metabolic disorder involving gut dysbiosis,

oxidative stress, inflammation, and impaired lipid metabolism.

The proposed schematic consolidates four major pathways consistently identified in in vitro, in vivo, and

clinical studies:

(1) inhibition of digestive enzymes (α-amylase and α-glucosidase),

(2) modulation of gut microbiota and intestinal barrier integrity,

(3) attenuation of oxidative stress, and

(4) regulation of metabolic pathways via SIRT1–AMPK activation and lipogenic gene suppression.

The hepatoprotective mechanisms of Caulerpa spp. against Non-Alcoholic Fatty Liver Disease (NAFLD) and

its inflammatory progression, Non-Alcoholic Steatohepatitis (NASH), are comprehensive, aligning with the

hypothesis which posits that the disease arises from numerous, parallel insults [23]. Caulerpa exerts its

protective effects not through a single target, but by simultaneously modulating four distinct, yet interconnected,

pathways.

First, as an upstream intervention, Caulerpa addresses the initial metabolic burden originating from the diet.

Bioactive compounds, including phenolics and polysaccharides, have been shown to effectively inhibit key

digestive enzymes, specifically -amylase and -glucosidase [24]. This action slows the breakdown of complex

carbohydrates in the gastrointestinal tract, leading to a blunted postprandial glucose spike. The immediate

consequence is a reduced demand for insulin, which in turn mitigates a primary driver for de novo lipogenesis

(the creation of new fat) in the liver.

Second, Caulerpa plays a crucial role in modulating the gut-liver axis, a critical communication highway that is

often compromised in NAFLD [27]. Evidence from studies on C. lentillifera reveals a dual-action benefit: it

enhances intestinal barrier integrity by upregulating the expression of tight-junction proteins like Occludin and

ZO-1, and it concurrently fosters a healthier gut microbiome by enriching beneficial populations, such

as Akkermansia [26]. This fortified barrier function significantly reduces the translocation of bacterial

endotoxins (LPS) from the gut into the portal circulation. By preventing this "leaky gut"

phenomenon, Caulerpa effectively diminishes the primary trigger for hepatic inflammation, dampening

the TLR4/NF-B signaling cascade within liver cells.

Third, Caulerpa provides direct hepatocellular protection by combating oxidative stress, a key factor that propels

the progression from simple fatty liver (steatosis) to the more dangerous inflammatory state of NASH [25]. The

seaweed's compounds bolster the liver's endogenous antioxidant defense system, demonstrably increasing the

activity of crucial enzymes like Superoxide Dismutase (SOD), Catalase, and Glutathione. Simultaneously, it

significantly lowers levels of malondialdehyde (MDA), a key marker of lipid peroxidation and cellular

damage [22]. This powerful antioxidant effect shields hepatocytes from damage by Reactive Oxygen Species

(ROS), preserving cellular integrity and reducing a major source of inflammation.

Finally, at the core of liver metabolism, Caulerpa directly addresses the accumulation of fat by

promoting metabolic regulation at the intracellular level. This is primarily achieved through the activation of

the AMPK and SIRT1 signaling pathways, which act as master regulators of cellular energy homeostasis [28].

This activation initiates a critical metabolic shift: it actively suppresses de novo lipogenesis by downregulating

the key transcription factors and enzymes responsible for fat synthesis (e.g., SREBP-1c, FAS, ACC), while

it simultaneously promotes fatty acid oxidation (the "burning" of fat for energy).

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In conclusion, the therapeutic potential of Caulerpa spp. for NAFLD/NASH lies in this synergistic, multi-target

approach. By combining upstream digestive enzyme inhibition, restoration of the gut-liver axis, potent

antioxidant defense, and a direct reprogramming of hepatic lipid metabolism, these pathways converge. The

unified outcome is a significant reduction in lipid accumulation (steatosis), decreased hepatic inflammation, and

improved systemic insulin sensitivity, all of which contribute to robust protection against the progression of

NAFLD to NASH [23].

Limitation

Although the existing preclinical evidence is promising, several significant limitations must be addressed before

the clinical potential of Caulerpa can be realized. First, the clinical data gap is substantial; this review identified

only one human clinical trial , which focused on obesity rather than diagnosed NAFLD or NASH patients.

Second, pharmacokinetic and bioavailability (PK/PD) challenges were unexplored in the existing studies. Key

bioactive compounds, such as sulfated polysaccharides, are large macromolecules generally known for poor oral

bioavailability. Future studies must quantify the absorption of these compounds and their concentrations in liver

tissue to validate that effective doses are systemically achievable. Third, the extreme dose heterogeneity in in

vivo studies (ranging from 65 mg/kg to 50 g/kg diets) makes the determination of a human-equivalent dose

(HED) nearly impossible. The high doses used in some animal models may not be practical or tolerable for

chronic supplementation in humans. Finally, toxicological and long-term safety considerations are entirely

unaddressed. While Caulerpa is edible, some species (particularly invasive strains) are known to accumulate

heavy metals or produce toxic secondary metabolites like caulerpicin and caulerpenyne as defense mechanisms.

The lack of formal long-term toxicology studies is a major barrier to regulatory approval as a nutraceutical.

Therefore, extraction standardization, phytochemical profiling, and rigorous safety assessments are urgently

required.

Future Research

To translate these promising preclinical findings into viable nutraceuticals or therapeutics, several key industrial

and research challenges must be addressed.

Extraction Standardization and Quality Control

A primary challenge is the lack of standardization. As seen in the reviewed studies, extraction methods vary

widely (e.g., different solvent macerations vs. Soxhlet), directly impacting the bioactive profile and potency.

Commercial development demands the establishment of validated, standardized green extraction protocols.

Furthermore, phytochemical fingerprinting (e.g., using HPLC or GC-MS) is essential to establish a consistent

compound profile and ensure batch-to-batch quality.

Scalability and Sustainability

Reliance on wild harvesting of Caulerpa is neither sustainable nor scalable for mass production. Industrial

scalability is entirely dependent on optimizing aquaculture techniques. Future research should focus on

improving cultivation yields while rigorously monitoring for potential contaminant accumulation (like heavy

metals) from seawater to ensure product safety.

Formulation and Delivery

Overcoming poor bioavailability (as discussed in Limitations) is critical for efficacy. Research must focus on

advanced formulations. Technologies such as nanoencapsulation or biopolymer delivery systems are crucial for

protecting bioactive compounds from degradation, enhancing solubility, and ensuring targeted delivery, thereby

improving overall bioefficacy.

Clinical Validation

Ultimately, all these efforts must culminate in larger, well-designed, multi-center randomized controlled trials

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(RCTs) in diagnosed NAFLD and NASH patient populations to validate safety, efficacy, and optimal dosage in

the target population.

Industrial Implications: Scalability, Standardization, and Sustainability

The therapeutic potential of Caulerpa spp. for metabolic liver disease must also be evaluated through the lens of

industrial feasibility. In order for Caulerpa-derived extracts to progress from preclinical studies to commercial

nutraceutical or pharmaceutical products, several large-scale challenges including extraction standardization,

production scalability, and sustainability must be systematically addressed. These considerations are essential to

ensure consistency, safety, and economic viability for future clinical and industrial applications.

Extraction Standardization and Quality Control

Current findings reveal substantial heterogeneity in extraction methods across studies, resulting in wide variation

in phytochemical profiles and bioactivity. Most research employs different solvents (water, ethanol, methanol,

ethyl acetate), extraction times, or temperatures, leading to inconsistent concentrations of key bioactive

constituents such as sulfated polysaccharides, carotenoids, peptides, and polyphenols. This variability poses a

major barrier to reproducibility and regulatory validation. Industrial translation therefore requires the

establishment of standardized extraction protocols based on Good Manufacturing Practices (GMP) and green

extraction technologies, including supercritical CO₂ extraction, microwave-assisted extraction, or ultrasound-

assisted extraction. These approaches improve yield, reduce solvent waste, and preserve thermolabile

compounds, making them ideal for large-scale production. Robust quality control must also be integrated using

analytical techniques such as HPLC, LC–MS/MS, or GC–MS to generate a stable phytochemical fingerprint that

ensures batch-to-batch consistency. This step aligns with regulatory expectations for botanical drug

development, where marker compounds must be identified and quantified to guarantee product reliability [21].

Scalability and Aquaculture Requirements

Large-scale production of Caulerpa cannot depend solely on wild harvesting, as this raises concerns about

ecological disturbance, seasonality, and variability in nutrient composition. Moreover, wild Caulerpa may

accumulate environmental contaminants such as heavy metals, pesticides, or microplastics, which compromise

extract safety and require extensive purification. To achieve industrial scalability, commercial development must

shift toward controlled aquaculture systems, including tank-based cultivation, integrated multi-trophic

aquaculture (IMTA), or long-line marine farming. These approaches allow for standardized nutrient conditions,

controlled light and salinity, and continuous monitoring to avoid contaminant accumulation. Aquaculture-based

production also ensures stable biomass supply while reducing ecological pressures on coastal ecosystems.

Studies in seaweed biotechnology demonstrate that optimized aquaculture can increase biomass yield by 40–

60% while improving polysaccharide uniformity and reducing heavy-metal uptake [29] Such models are directly

applicable to Caulerpa spp. and necessary for its future commercialization.

Sustainability and Environmental Considerations

Sustainable production is especially important because certain Caulerpa species (e.g., C. taxifolia) are known to

behave as invasive organisms in non-native waters. Large-scale harvesting without proper ecological assessment

may risk habitat disturbance or biodiversity loss. Therefore, environmental risk assessment and Life Cycle

Assessment (LCA) must be incorporated into cultivation planning to ensure low carbon footprint, low nutrient

discharge, and minimal ecological disturbance. Additionally, valorization of residual biomass such as converting

spent seaweed pulp into animal feed, compost, or biodegradable packaging may enhance sustainability and

economic value, aligning with circular bioeconomy principles recommended by United Nations Environment

Programme [30].

Formulation, Delivery, and Bioavailability Challenges

Even with scalable biomass production, formulation challenges remain. Bioactive polysaccharides from

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Caulerpa generally possess large molecular weights and limited gastrointestinal absorption. To improve oral

bioavailability and therapeutic potency, advanced delivery systems including nanoencapsulation, liposomal

carriers, or biopolymer-based hydrogels should be explored. These technologies can protect compounds from

degradation, enhance solubility, and enable targeted hepatic delivery, improving overall clinical efficacy.

Translational and Regulatory Pathways

Finally, translational success will depend on rigorous toxicological evaluation, standardized dosage

determination, and multi-center clinical trials. Regulatory agencies such as the FDA and EMA require

comprehensive safety, pharmacokinetic, and manufacturing data before approving botanical therapeutics.

Establishing standardized cultivation, extraction, and quality-control systems is therefore not only scientifically

necessary but also essential for meeting regulatory benchmarks for future Caulerpa-based interventions.

CONCLUSION

This review demonstrates that Caulerpa spp. contains bioactive compounds with strong hepatoprotective and

antihyperglycemic effects supported by in vitro, in vivo, and early clinical evidence. Through antioxidant

activity, metabolic regulation, enzyme inhibition, and gut–liver axis modulation, Caulerpa effectively reduces

oxidative stress, lipid accumulation, and glucose dysregulation, key of NAFLD and NASH progression. While

findings are consistently positive, clinical research remains limited and extract standardization is still required.

Future clinical trials are essential to evaluate long-term safety, establish clinically relevant therapeutic dosages,

and determine if these preclinical findings can be effectively translated into nutraceuticals for metabolic liver

disease.

Conflicts of Interest

The Authors declare no potential conflict of interest concerning the contents, authorship, and/or publication of

this article.

Funding

The authors declared that this study has received no financial support.

Data Availability Statement

The data supporting this paper is available in the cited references.

Ethical Approvals

Not applicable

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