Hepatocyte-derived lipid droplets in MASH: macrophage sensing and inflammation

Metabolic dysfunction-associated steatohepatitis (MASH) develops through interactions between hepatocyte injury and hepatic immune responses. Lipid droplets (LDs) exposed or released from damaged hepatocytes provide a potential link between lipid accumulation and macrophage-mediated inflammation. Experimental studies indicate that these structures can both promote disease-associated macrophage responses and attenuate inflammatory signaling. This mini-review examines how hepatocyte-derived LDs influence macrophage sensing, uptake, and inflammatory responses in MASH. We discuss the contribution of membrane-spanning 4-domains A7 (MS4A7) to NLRP3 inflammasome activation and disease progression, alongside evidence that LD treatment suppresses inflammatory responses in cultured macrophages. Triggering receptor expressed on myeloid cells 2 (TREM2) supports this suppression without being required for LD uptake in the tested system, while reduced MS4A7 expression contributes to the attenuation of inflammatory signaling. These findings distinguish LD internalization from its downstream immune effects and warrant separate consideration from the efferocytosis of intact apoptotic hepatocytes. We examine experimental conditions and macrophage states as possible explanations for differing outcomes and identify unresolved questions about LD recognition and relevance to human disease. Finally, we consider therapeutic strategies that limit pathogenic macrophage activation while preserving beneficial clearance functions. Defining the molecular basis of LD sensing and establishing its consequences in vivo will be essential for translating this form of hepatocyte–macrophage communication into immunological interventions for MASH.