Co-intake of lauric and linoleic acids exacerbates hepatotoxicity in the metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH), an advanced manifestation of metabolic dysfunction-associated steatotic liver disease (MASLD), affects approximately 30% of adults worldwide. Fatty acids, as important nutrients, are absorbed and utilized in a complex mixture daily. Medium-chain fatty acids are recommended for patients with lipid metabolism disorders due to their favorable metabolic properties and linoleic acid (LA-l, an essential fatty acid) is commonly consumed, but their combined effects in MASH remain unclear. Therefore, in this study, we employed multi-level models and lipidomics to investigate the combined effects of lauric acid (LA-m) and LA-l under normal and MASH conditions. The results revealed that co-intake of LA-m and LA-l exacerbated hepatotoxicity specifically in MASH, but not in healthy conditions, indicating metabolic status may determine susceptibility. Mechanistically, this combination increased membrane sphingolipid accumulation under the MASH diet, inducing endoplasmic reticulum stress, and ultimately triggering hepatotoxicity. Moreover, the combination increased ACSL4 expression to generate AA/AdA-PE, suggesting that LA-m may make hepatocytes more sensitive to ferroptosis by promoting the esterification of LA-l. Collectively, these findings provide caution in the concomitant use of LA-m and LA-l in MASH patients.