Phenylethanoid glycosides: A mini review on their anti-liver injury effects and underlying mechanisms

Phenylethanoid glycosides (PhGs) are natural sugar‑containing compounds with diverse structures and broad pharmacological activities. This review summarizes their anti‑liver injury effects. Key compounds (acteoside, echinacoside, salidroside, forsythoside A) act through antioxidant (Nrf2), anti‑inflammatory (NF‑κB), anti‑apoptotic, and anti‑fibrotic (TGF‑β/Smad) pathways. Preclinical evidence is promising, but clinical translation is hindered by low bioavailability and complex metabolism. Future directions include structural optimization and gut microbiota studies.

Introduction
Liver diseases are a major global health burden. Current therapies have limitations, driving interest in natural hepatoprotective agents. PhGs, found in many medicinal plants, exhibit anti‑inflammatory, antioxidant, and hepatoprotective activities. This review systematically covers their anti‑liver injury effects and mechanisms.

Chemical Structure and Typical Compounds
PhGs consist of phenylethyl alcohol, cinnamic acid (usually caffeic acid), and glycosyl moieties (glucose as central unit). Representative compounds:

• Acteoside (most studied; caffeoyl + rhamnose)

• Echinacoside (triglycoside from Echinacea)

• Salidroside (simplest; highest bioavailability)

• Forsythoside A (macrocyclic; neuroprotective)

Anti-liver Injury Activities

• Total extracts: From Acanthus ilicifolius reduce ALT/AST, MDA, TNF‑α, IL‑1β; from Cistanche tubulosa inhibit TGF‑β1/Smad (anti‑fibrotic) and induce apoptosis via MAPK.

• Acteoside: Superior to silybinin in CCl₄ models; inhibits CYP2E1; reduces NF‑κB in alcoholic hepatitis; metabolites (hydroxytyrosol) show stronger effects than parent compound.

• Echinacoside: Anti‑fibrotic (TGF‑β/Smad); inhibits apoptosis/inflammation in acute liver injury; antioxidant; suppresses HCC.

• Forsythoside A: Attenuates GalN/LPS injury via NF‑κB/Nrf2; alleviates MAFLD via IL‑17/MAPK and metabolic remodeling.

• Cistanoside A: Protects against CCl₄/alcohol toxicity via radical scavenging, anti‑lipid peroxidation, and mitochondrial protection.

• Tubuloside A/B: A activates Nrf2/HO‑1 against oxidative injury; B inhibits HCC migration via Hippo‑YAP.

Mechanisms
PhGs act via multi‑target pathways:

• Oxidative stress: Nrf2/HO‑1 activation, SOD↑, MDA↓

• Inflammation: NF‑κB inhibition, TNF‑α/IL‑1β↓

• Apoptosis: Bcl‑2/Bax regulation, caspase‑3 inhibition

• Fibrosis: TGF‑β/Smad inhibition

• Metabolism: IL‑17/MAPK modulation, lipid homeostasis

Structure-Activity

• Caffeoyl > feruloyl; disaccharide > mono‑/trisaccharide.

• Acteoside (4,5‑dihydroxyphenylethanol + caffeoyl + rhamnose) is water‑soluble and crosses the BBB.

Limitations & Future

• Limitations: Mostly preclinical; variable models; limited PK/PD data.

• Future: Clinical trials; structural optimization for better bioavailability; study gut microbiota roles; use AI for target‑specific design.

Conclusions
PhGs show strong hepatoprotective potential through multi‑target mechanisms (oxidative stress, inflammation, apoptosis, fibrosis). Clinical translation requires overcoming low bioavailability and metabolic complexity. Future work should focus on structural optimization, formulation improvement, and systematic in vivo validation.

Full text:

https://www.xiahepublishing.com/2835-6357/FIM-2025-00063

The study was recently published in the Future Integrative Medicine.

Future Integrative Medicine (FIM) is the official scientific journal of the Capital Medical University. It is a prominent new journal that promotes future innovation in medicine.It publishes both basic and clinical research, including but not limited to randomized controlled trials, intervention studies, cohort studies, observational studies, qualitative and mixed method studies, animal studies, and systematic reviews.

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