Identification of a natural PLA2 inhibitor from the marine fungus Aspergillus sp.c1 for MAFLD treatment that suppressed lipotoxicity by inhibiting the IRE-1a/XBP-1s axis and JNK signaling

Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease(MAFLD).However,there are few reported lipotoxicity inhibitors.Here,we identified a natural anti-lipotoxicity candidate,HN-001,from the marine fungus Aspergillus sp.C1.HN-001 dose-and time-dependently reversed palmitic acid(PA)-induced hepatocyte death.This protection was associated with IRE-1a-mediated XBP-1 splicing inhibition,which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation.Knockdown of XBP-1s attenuated lipotoxicity,but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes.Notably,the ER stress and lipotoxicity amelioration was associated with PLA2.Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity,reduced lysophosphatidylcholine(LPC)level,subsequently ameliorated lipotoxicity.In contrast,overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001.Additionally,HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway.In vivo,chronic administration of HN-001(i.p.)in mice alleviated all manifestations of MAFLD,including hepatic steatosis,liver injury,inflammation,and fibrogenesis.These effects were correlated with PLA2/IRE-1a/XBP-1s axis and JNK signaling suppression.These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity,and provide a natural structural basis for developing anti-MAFLD candidates.