Toxicology in vitro : an international journal published in association with BIBRA · 2026
Microbiota-derived Indole-3-propionic acid improves FFA-induced liver injury in an in vitro model of nonalcoholic fatty liver disease by activating PINK1/parkin-mediated mitophagy.
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Liu Qilin, Wu Dahai, Teng Linhua, Lin Gengyang, Huang Huali, Liang Zhihai
Аннотация
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern, and its pathology is associated with impaired hepatic mitochondrial function and disrupted mitophagy. Emerging evidence highlights gut microbiota-derived metabolites as key regulators of NAFLD progression. Indole-3-propionic acid (IPA), a microbiota-derived tryptophan metabolite, has been linked to NAFLD development. However, its influence on mitophagy remains poorly defined.
METHODS: In vitro, HepG2 cells were treated with free fatty acid (FFA) to establish a NAFLD model, followed by IPA treatment. The mRNA and protein expression levels were analyzed by qRT-PCR, Western blot, and immunofluorescence staining. Cell viability, oxidative stress, apoptosis, and mitochondrial function were assessed via CCK-8, ELISA, flow cytometry, and JC-1 staining. PINK1-USP4 interaction and ubiquitination were examined using co-IP and ubiquitination assays.
RESULTS: Serum IPA levels were significantly reduced in NAFLD patients. In FFA-treated HepG2 cells, IPA attenuated oxidative injury while restoring mitochondrial function. Mechanistically, IPA activated PINK1/Parkin-mediated mitophagy by upregulating USP4, which stabilized PINK1 via deubiquitination. PINK1 or USP4 knockdown abolished IPA's protective effects against FFA-induced oxidative injury and mitophagy impairment in hepatocytes.
CONCLUSION: IPA alleviated FFA-induced oxidative injury in hepatocytes by activating PINK1/Parkin-mediated mitophagy via USP4-dependent PINK1 deubiquitination. These findings reveal a gut microbiota-mitochondria axis in NAFLD and suggest IPA as a potential therapeutic strategy targeting the USP4-PINK1 pathway.
METHODS: In vitro, HepG2 cells were treated with free fatty acid (FFA) to establish a NAFLD model, followed by IPA treatment. The mRNA and protein expression levels were analyzed by qRT-PCR, Western blot, and immunofluorescence staining. Cell viability, oxidative stress, apoptosis, and mitochondrial function were assessed via CCK-8, ELISA, flow cytometry, and JC-1 staining. PINK1-USP4 interaction and ubiquitination were examined using co-IP and ubiquitination assays.
RESULTS: Serum IPA levels were significantly reduced in NAFLD patients. In FFA-treated HepG2 cells, IPA attenuated oxidative injury while restoring mitochondrial function. Mechanistically, IPA activated PINK1/Parkin-mediated mitophagy by upregulating USP4, which stabilized PINK1 via deubiquitination. PINK1 or USP4 knockdown abolished IPA's protective effects against FFA-induced oxidative injury and mitophagy impairment in hepatocytes.
CONCLUSION: IPA alleviated FFA-induced oxidative injury in hepatocytes by activating PINK1/Parkin-mediated mitophagy via USP4-dependent PINK1 deubiquitination. These findings reveal a gut microbiota-mitochondria axis in NAFLD and suggest IPA as a potential therapeutic strategy targeting the USP4-PINK1 pathway.