Therapeutic applications and pharmacological actions of luteolin in liver diseases

Luteolin is a dietary flavonoid with hepatoprotective effects against steatosis, inflammation, fibrosis, and hepatocellular carcinoma. This review synthesises its pharmacology across liver diseases, mapping mechanisms to disease contexts and identifying translational challenges. Luteolin acts through Nrf2 antioxidant defence, NF‑κB/NLRP3 anti‑inflammation, TGF‑β/Smad anti‑fibrosis, and LXR/AMPK metabolic regulation. Despite robust preclinical evidence, clinical translation is hindered by scarce RCTs, limited understanding of metabolite bioactivity, and lack of evaluated delivery systems.

Introduction

Liver diseases impose a major global burden, with limited options for MASLD, fibrosis, and drug‑induced injury. Luteolin, found in vegetables and herbs, exhibits hepatoprotective, anti‑inflammatory, antifibrotic, and antitumour activities. However, translation is hindered by fragmented mechanisms, poor bioavailability, and scarce human trials.

Liver Diseases Targeted by Luteolin

NAFLD/MASLD: Luteolin reduces steatosis and inflammation via PI3K/AKT/FoxO1, LXR/SREBP‑1c suppression, AMPK activation, and gut microbiota modulation. A human study showed a luteolin‑containing supplement improved liver parameters.

Alcoholic Liver Disease: Luteolin reduces oxidative stress and lipogenesis via Nrf2 stabilisation. Nanoparticle formulations enhance efficacy.

Drug/Toxin‑Induced Injury: Luteolin protects against CCl₄, APAP, heavy metals, and other toxins via Nrf2 activation, ferroptosis inhibition (SLC7A11/GPX4), and apoptosis suppression.

Sepsis and Ischaemia‑Reperfusion: Luteolin inhibits TLR4/NF‑κB and NLRP3, promotes M2 polarisation, and reduces IR injury via ERK/PPARα.

Liver Fibrosis: Luteolin inhibits HSC activation via STAT3, AKT/mTOR, and TGF‑β/Smad, and promotes ECM degradation. Nanodelivery systems enhance efficacy.

Hepatocellular Carcinoma: Luteolin induces apoptosis, senescence, and ferroptosis; inhibits metastasis; and enhances CD8⁺ T‑cell immunity. Key targets include AKT1/SRC, MEF2D/AMOTL2/YAP, and the miR‑6809‑5p/FLOT1/FAK axis.

Viral Hepatitis: Luteolin inhibits HBV replication via ERK‑mediated HNF4α downregulation.

Pharmacological Actions

• Antioxidant: Activates Nrf2/ARE, upregulates HO‑1/GCL, inhibits ferroptosis.

• Anti‑inflammatory: Suppresses NF‑κB, TLR4, NLRP3; promotes M2 polarisation.

• Metabolic: Suppresses SREBP‑1c, activates AMPK/PGC‑1α, improves insulin sensitivity, inhibits adipose lipolysis via HTR2B.

• Anti‑tumour: Induces apoptosis, senescence, ferroptosis; inhibits EMT and metastasis.

• Anti‑apoptotic in normal hepatocytes: Protects against ER stress and apoptosis.

• Gut‑liver axis: Restores microbiota and intestinal barrier integrity.

Pharmacokinetics and Challenges

Luteolin has very low oral bioavailability due to extensive first‑pass metabolism. Novel formulations (nanoparticles, MOFs, exosomes, targeted liposomes) improve solubility and targeting but require safety evaluation.

Limitations and Future Directions

Most evidence is preclinical; isolated luteolin lacks human trials. Heterogeneity limits comparisons. Future priorities: rigorous RCTs, synergistic combinations, metabolite activity studies, cell‑type‑specific delivery, and long‑term safety assessments.

Conclusions

Preclinical evidence supports luteolin as a multi‑target agent for liver diseases via Nrf2, NF‑κB, AMPK, TGF‑β, and gut‑liver axis modulation. Clinical translation requires advanced delivery systems, synergistic combinations, and rigorous human trials.

Full text

https://www.xiahepublishing.com/2572-5505/JERP-2025-00068

The study was recently published in the Journal of Exploratory Research in Pharmacology.

Journal of Exploratory Research in Pharmacology (JERP) publishes original innovative exploratory research articles, state-of-the-art reviews, editorials, short communications that focus on novel findings and the most recent advances in basic and clinical pharmacology, covering topics from drug research, drug development, clinical trials and application.

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