Macrophage efferocytosis in MASH: balancing inflammation resolution and fibrosis

Apoptotic hepatocytes accumulate in metabolic dysfunction-associated steatohepatitis (MASH), where impaired macrophage efferocytosis can prolong inflammatory injury. Restoring their clearance offers a potential therapeutic approach, although the receptors involved also engage signaling pathways that influence fibrosis. In experimental MASH, restoration of T cell immunoglobulin and mucin domain containing 4 (TIM4) enhances apoptotic hepatocyte removal and promotes interleukin-10 production, thereby limiting hepatic stellate cell activation. Inflammatory cleavage of triggering receptor expressed on myeloid cells 2 (TREM2) compromises efferocytosis and sustains liver inflammation. Mer tyrosine kinase (MerTK) signaling can promote transforming growth factor β1 (TGF-β1) production and fibrogenic stellate cell responses. These findings highlight the need to evaluate cell clearance and receptor signaling as related but distinct determinants of disease progression. This mini review compares the evidence for TIM4, TREM2, and MerTK in MASH, with attention to macrophage heterogeneity and the distinction between experimental disease progression and human fibrosis-stage evidence. Comparisons with atherosclerosis illustrate how tissue context may alter the consequences of receptor targeting. We discuss strategies to restore TIM4 function and protect TREM2 from cleavage, alongside gaps in human evidence. Whether effective efferocytosis can be preserved while profibrotic signaling is restrained remains unresolved and requires direct testing to guide selective immune interventions in MASH.