Authors
Reeju Amatya, Kyoung Ah Min, Meong Cheol Shin
Published in
International journal of molecular sciences. Volume 27. Issue 16. Aug 08, 2026. Epub Aug 08, 2026.
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are a growing global health burden with extremely limited pharmacological options, thereby indicating an urgent need for innovative therapeutic strategies. Hepatokines are liver-derived secreted proteins that coordinate metabolic communication between the liver and peripheral organs and have emerged as mechanistically compelling therapeutic candidates. This review comprehensively examines beneficial hepatokines with protective roles in MASLD/MASH, detailing their molecular mechanisms of action across key metabolic tissues, including their effects on hepatic lipid metabolism, insulin sensitivity, inflammatory signaling, and fibrogenesis. We further discuss the fundamental pharmacokinetic barriers of these protein therapeutics, particularly their susceptibility to renal clearance and proteolytic degradation. Furthermore, we examine the principal half-life extension strategies to overcome these limitations, with particular emphasis on their clinical application to FGF21-based drug candidates that are currently advancing through phase 3 trials. Overall, this review highlights the therapeutic potential of hepatokine-based biologics and the critical role of protein engineering in translating these mechanistic insights into durable, clinically viable treatments for MASLD/MASH.
PMID:
42653122
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.
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