13(S)-HODE Generated by Rhizopus microsporus var. rhizopodiformis Aggravates MASLD via the Elane-PAR2-SREBP-1c Axis

ABSTRACT: Abstract Objective:Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) poses a major public health challenge. Increasing data suggest a role of gut fungi in liver disease, yet their diversity and biological function in MASLD are still poorly understood. Methods:Internal transcribed spacer (ITS) sequencing was conducted on fecal samples from 107 individuals with MASLD and 120 matched healthy controls (HC). A high-fat diet (HFD)-induced MASLD mouse model was established, and multi-omics analyses, including liver transcriptomic sequencing, qPCR, WB, and immunofluorescence, were performed to elucidate the molecular mechanisms underlying key gut fungi associated with MASLD. Microbial-derived metabolites involved in MASLD were investigated through multi-omics analyses in vitro and in vivo. Results:MASLD patients showed significantly reduced fungal diversity and richness compared with HC. The gut mycobiota of MASLD patients exhibited a marked increase in the pathogenic genus Rhizopus, particularly Rhizopus microsporus var. rhizopodiformis and R. microsporus var. chinensis, which were positively associated with hepatic steatosis and body mass index (BMI). Fecal microbiota transplantation from MASLD patients into antibiotic-treated mice induced MASLD-like phenotypes, while amphotericin B treatment mitigated disease progression. Oral administration of R. microsporus var. rhizopodiformis in HFD-fed mice aggravated gut dysbiosis, disrupted intestinal barrier integrity, and activated hepatic SREBP-1c signaling, leading to upregulation of key lipogenic enzymes ACC1 and FASN. These changes were mediated through a pro-inflammatory cascade involving the hepatic LPS–TLR4–NF-κB axis and enhanced neutrophil degranulation. 13(S)-HODE, potentially identified as a key metabolite produced by R. microsporus var. rhizopodiformis, aggravated MASLD. 13(S)-HODE promotes neutrophil trafficking to the liver, where released elastase (Elane) directly cleaves and activates the master transcription factor SREBP-1c via a non-canonical PAR2 signaling pathway, leading to uncontrolled hepatic de novo lipogenesis. Conclusion:Our findings suggest that Rhizopus microsporus var. rhizopodiformis and its candidate metabolite 13(S)-HODE are associated with MASLD progression, potentially via the Elane-PAR2-SREBP-1c axis. These observations provide a preliminary basis for further investigating the role of gut fungi in MASLD pathogenesis.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS15516 | MetaboLights | 2026-09-01

REPOSITORIES: MetaboLights