Adipokine-Based Therapeutics for MASLD: Bridging Adipokine Resistance and FGF21 Half-Life Extension Strategies

Metabolic dysfunction-associated steatotic liver disease (MASLD) arises from the convergence of hepatic lipid overload, insulin resistance, mitochondrial dysfunction, oxidative stress, and chronic low-grade inflammation, yet effective pharmacotherapy remains limited. Increasingly, adipose tissue is recognized not as a passive lipid depot but as an endocrine organ whose secreted adipokines regulate hepatic lipid and glucose metabolism, inflammatory signaling, and fibrogenesis through pathways including AMP-activated protein kinase (AMPK), peroxisome proliferator–activated receptor-α (PPARα), protein kinase B (Akt), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Restoring adipokine activity can reduce hepatic triglyceride levels, enhance fatty acid β-oxidation, improve insulin sensitivity, and attenuate fibrotic remodeling, but the translational maturity of individual targets varies considerably. Among these, only the fibroblast growth factor 21 (FGF21) programme can currently be described as clinically advanced, having reached Phase 2b/3 human trials; adiponectin remains the most mechanistically characterized hepatoprotective adipokine, but adiponectin-directed agents (adiponectin receptor (AdipoR) agonists, adiponectin mimetics) are still preclinical. Two interlocking barriers separate this biological rationale from durable therapeutic application: adipokine resistance, which appears to be a systemic feature of advanced disease that blunts signaling across multiple axes, and the short plasma half-lives and proteolytic susceptibility of native adipokines. This review examines the molecular mechanisms, pharmacokinetics, and receptor-sensitization strategies relevant to adipokine-based therapy, including PEGylation, glycoPEGylation, fragment crystallizable (Fc)-fusion, and rational combination regimens, positioning adipokine-targeted therapy as an attractive approach to MASLD treatment.