The multifaceted roles of interleukin-36 in liver diseases: from pathogenesis to therapeutic potential.

Interleukin-36 (IL-36), a member of the IL-1 cytokine superfamily, has emerged as a critical regulator of immune and inflammatory responses in the liver. Accumulating evidence reveals that IL-36 orchestrates hepatic inflammation, injury, and repair in a highly context-dependent manner. We propose a unified "IL-36 switch" framework wherein functional outcomes are determined by three interrelated factors: the cellular source of IL-36 ligands (neutrophil-derived in acute settings versus hepatocyte-derived in chronic disease), the duration and magnitude of signaling, and the evolving cellular composition of the diseased liver. This review synthesizes recent findings elucidating the context-dependent functions of IL-36 across the spectrum of liver pathologies. In acute liver injury, transient IL-36 signals maintain immune homeostasis and promote tissue repair, whereas sustained signaling in chronic conditions drives pathological inflammation, steatosis, and fibrogenesis. The Toll-like receptor 3-IL-36-neutrophil extracellular traps axis in acute liver failure and IL-36-mediated gut-liver axis dysregulation in cirrhosis represent novel pathogenic mechanisms. In hepatocellular carcinoma, compartment-specific discrepancies (low intratumoral but high circulating IL-36) and ligand-specific effects reveal complex tumor-immune interactions. We critically evaluate the translational potential of IL-36 targeting, considering evidence from successful IL-36R blockade in pustular psoriasis, while emphasizing critical caveats including species-specific differences between murine models and human disease, infection risk, and the need to preserve homeostatic functions. Finally, we identify key knowledge gaps and propose a future research program to investigate the therapeutic potential of IL-36 modulation in liver diseases.