Liver sinusoidal endothelial cells: Central mediators of MASLD pathogenesis and sepsis susceptibility.

Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, remains a critical global health challenge with mortality rates exceeding 20 % in affected populations. The liver, a frontline immune organ, plays a dual role in sepsis-acting as both a guardian against systemic infections and a vulnerable target for injury. Metabolic dysfunction-associated steatotic liver disease (MASLD), affecting nearly 30 % of the global population, significantly amplifies sepsis susceptibility, with MASLD patients exhibiting doubled infection-related mortality rates compared to healthy controls. Central to this nexus are liver sinusoidal endothelial cells (LSECs), specialized gatekeepers of hepatic immune surveillance and metabolic homeostasis. In MASLD, LSECs undergo significant structural and functional changes, triggered by lipotoxicity, oxidative stress, and chronic inflammation. These structural and functional derangements impair pathogen clearance, disrupt immune regulation, and promote systemic leakage of gut-derived toxins. LSECs further orchestrate pathogenic crosstalk with hepatocytes, Kupffer cells (KCs) and hepatic stellate cells (HSCs), fueling hepatic immune dysregulation and increasing sepsis risk. This review synthesizes evidence positioning LSECs as pivotal mediators bridging MASLD progression to sepsis vulnerability, highlighting therapeutic strategies targeting LSECs dysfunction to mitigate infection risks in metabolic liver disease.