Myeloid CD36 deficiency alleviates hepatic fibrosis by promoting adaptive immunity of macrophage

Background & Aims: Hepatic fibrosis presents a major global health challenge, yet effective preventive and therapeutic strategies remain limited. Hepatic macrophages, which play a dual role in fibrosis progression, are central to understanding its pathogenesis. This study aimed to elucidate how macrophage lipid metabolism mediated by CD36 regulates immune function and fibrosis development. Approach & Results: We demonstrated that macrophages engulf lipids secreted by hepatic stellate cells (HSCs) via the CD36 receptor, resulting in enhanced lipid peroxidation, ferroptosis, and diminished antigen-presenting capacity, thereby impairing CD8⁺ T cell function. Conversely, CD36 deficiency restored antigen presentation through activation of the cGAS–STING pathway. Single-cell RNA sequencing further revealed that loss of CD36 in myeloid cells upregulated MHC-I-related gene expression in macrophages and promoted CD8⁺ T cell activation within the fibrotic liver microenvironment. Macrophage-specific CD36 knockout protected mice from fibrosis progression. In patients with liver cirrhosis, histological and serological analyses showed elevated CD36 expression, underscoring its clinical relevance. Conclusions: CD36-driven lipid uptake reprograms macrophage metabolism, leading to ferroptosis and impaired adaptive immunity. Targeting CD36 restores macrophage antigen-presenting function and enhances CD8⁺ T cell activation, identifying CD36 as a potential therapeutic target for hepatic fibrosis. The clinical trial was registered in the Research Registry (researchregistry10830).