Reviving peroxisome proliferator-activated receptors in fatty liver disease: From herbal formula to nuclear receptor targeting

Abstract

Due in large part to its intricate metabolic and inflammatory pathogenesis, metabolic dysfunction-associated fatty liver disease (MAFLD), the most common chronic liver disease in the world, still lacks a widely effective pharmacological treatment. Present mechanistic evidence that Lianhe Xiaozhi ointment (LXO), a formulation derived from traditional Chinese medicine, improves MAFLD by coordinating the activation of peroxisome proliferator-activated receptor alpha (PPARα). The authors show that LXO increases hepatic fatty acid oxidation and ketogenesis while inhibiting inflammatory signaling using an integrated systems approach that combines network pharmacology, hepatic transcriptomics, experimental models, and gut microbiota profiling. Significantly, LXO links intestinal metabolism to hepatic metabolic control by altering the gut microbiota and increasing endogenous fatty acid ligands, which further activate PPARα. In addition to repositioning PPARα as a key metabolic-immune hub, this study shows how multicomponent therapies may be able to overcome the drawbacks of single-target approaches in the treatment of MAFLD.

Keywords: Metabolic dysfunction-associated steatotic liver disease; Peroxisome proliferator-activated receptor alpha; Fatty acid oxidation; Inflammation; Traditional Chinese medicine; Lianhe Xiaozhi ointment

Core Tip: The efficacy of single-target therapies is limited by interconnected metabolic, inflammatory, and gut-derived mechanisms driving metabolic dysfunction-associated fatty liver disease. According to the study covered in this editorial, the hepatoprotective effects of Lianhe Xiaozhi ointment are mediated through peroxisome proliferator-activated receptor alpha (PPARα), a key metabolic-immune hub. This work offers a systems-based therapeutic framework by improving hepatic fatty acid oxidation, reducing inflammatory signaling, and altering the gut microbiota to raise endogenous PPARα ligands. These results reinforce the gut microbiota-fatty acid-PPARα axis as a promising target for future metabolic dysfunction-associated fatty liver disease interventions and support physiological, multilevel activation of PPARα.