Emerging Molecular Targets in MASH/NASH: Linking Pathogenic Mechanisms to Therapeutic Strategies for Improved...

Metabolically Dysfunctional-Associated Steatohepatitis (MASH), affecting approximately 5.27% of the global population, represents a critical unmet medical need with limited therapeutic options. The complex pathophysiology involving multiple interconnected pathways necessitates innovative therapeutic approaches beyond traditional targets. This review comprehensively examines emerging pharmacological targets for MASH treatment, focusing on novel mechanisms that address key pathogenic processes, including lipogenesis, inflammation, endoplasmic reticulum stress, and immune cell recruitment. We conducted a systematic analysis of preclinical and clinical evidence for six promising therapeutic targets: cyclophilins, ATP citrate lyase (ACLY), NLRP3 inflammasome, X-box binding protein 1 (XBP1), farnesoid X receptor (FXR), and chemokine receptors (CCR). Cyclophilin inhibitors (CRV431, NV556) demonstrate anti-fibrotic efficacy in Phase 2A trials by targeting mitochondrial dysfunction and collagen synthesis. ACLY inhibition offers advantages over acetyl-CoA carboxylase targeting by upstream modulation of de novo lipogenesis, with bempedoic acid showing clinical promise. NLRP3 inflammasome inhibitors (MCC950, JT001, GDC-2394) effectively reduce hepatic inflammation through caspase-1/IL-1β pathway modulation. XBP1 targeting addresses ER stress-mediated lipogenesis and inflammation crosstalk. FXR agonists (obeticholic acid, cilofexor, tropifexor) demonstrate robust clinical efficacy in improving steatosis, inflammation, and fibrosis. Chemokine receptor antagonists (cenicriviroc, AZD5069) show potential in reducing inflammatory cell recruitment, though mixed clinical results highlight the complexity of immune modulation. These novel targets represent a paradigm shift in MASH therapeutics, offering mechanistically distinct approaches that could enable personalized treatment strategies. The advanced clinical development of several candidates, particularly FXR agonists and cyclophilin inhibitors, suggests near-term therapeutic breakthroughs. Future combination therapies targeting multiple pathways simultaneously may optimize treatment efficacy for this multifaceted disease.