| Summary: | Manganese (Mn) toxicity thresholds are established for healthy populations, yet individuals with metabolic disorders may exhibit heightened vulnerability. This study investigated whether environmentally relevant Mn concentrations exacerbate the progression from simple steatosis to steatohepatitis through lipotoxic mechanisms. Using oleic acid (OA)-induced steatotic HepG2 cells exposed to 40 μM/L Mn, we employed integrated cytotoxicity assays, along with metabolomics and lipidomics. While neither Mn nor OA alone caused significant cellular injury, their combination triggered marked lipotoxicity. Mn co-exposure with OA significantly exacerbated lipid accumulation (2.1-fold triglyceride increase) despite paradoxically suppressing DGAT1/2 expression (60–70 % decrease). This disruption in triglyceride synthesis redirected lipids toward toxic intermediates: diacylglycerols (230 % increase) and free fatty acids (195 % increase), with concurrent lysophospholipid overproduction (170 % LPC18:3 increase). The accumulation of lipotoxic species induced oxidative stress (180 % ROS increase, 210 % MDA increase), activated the IRE1α-CHOP endoplasmic reticulum stress pathway (250 % increase), and triggered inflammatory cascades (200 % IL-6, 180 % IL-8 increase). These findings demonstrate a novel paradigm where Mn acts as an environmental modifier that promotes progression from simple steatosis toward inflammatory liver injury characterized by lipotoxicity, ER stress, and elevated inflammatory markers in metabolically compromised cells. This transformation of subtoxic exposures into potent lipotoxicity catalysts highlights the urgent need for disease-specific environmental exposure thresholds for metabolically vulnerable populations.
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