DECODING IMMUNE DYSREGULATION IN FATTY LIVER DISEASE: EMERGING THERAPEUTIC TARGETS AND STRATEGIES

Abstract

Fatty liver disease, formally recognized as metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory phenotype steatohepatitis (MASH), represents a leading indication for liver transplantation worldwide. The transition from benign steatosis to necroinflammation is driven by hepatocyte lipotoxicity and a profound breakdown in hepatic immune tolerance. In this Review, we discuss the cellular heterogeneities and functional dynamics of liver-resident and recruited myeloid cells, highlighting how specific transcriptomic signatures, such as TREM2 and CD9, delineate pathogenic functions and scar-associated macrophage accumulation. We outline the molecular sentinels of metabolic injury, including the NLRP3 inflammasome and cGAS–STING pathways, which translate sterile danger signals into amplified fibrotic damage. Furthermore, we explore the often-overlooked contributions of natural killer cells, innate lymphoid cells, and the platelet-leukocyte axis to MASH immunopathology. While thyroid hormone receptor-beta (THR-β) agonists and incretin-based therapies establish a new metabolic standard of care, their direct immunological effects remain incomplete. Consequently, the therapeutic frontier is shifting toward precision immunomodulation targeting the CCL2–CCR2 axis, profibrotic interleukin-11 (IL-11), and autoreactive T cell compartments. Finally, we contextualize the translational challenges posed by human MASH heterogeneity and inadequate preclinical models, predicting how spatiotemporal insights into liver immunity will define future curative strategies.