Lactate-driven protein lactylation contributes to aniline-induced hepatic metabolic dysfunction.

Abstract

Aniline is a widely distributed aromatic amine pollutant with recognized hepatotoxic potential, but the molecular events linking aniline exposure to hepatic metabolic dysfunction remain incompletely defined. Protein lactylation links lactate metabolism to cell regulation and may participate in exposure-related metabolic remodeling. Here, mouse models and short-term hepatocyte experiments (5 and 10 mmol/L aniline) were integrated with transcriptomics, metabolomics, lactylomics, Mendelian randomization, and single-cell transcriptomics to investigate lactate-associated responses. Aniline disrupted hepatic metabolic homeostasis and produced steatotic liver injury accompanied by oxidative stress, mitochondrial dysfunction, and lipid metabolic abnormalities. In cells, aniline decreased early growth response 1 (EGR1), increased lactate dehydrogenase A (LDHA), promoted lactate accumulation, and enhanced global protein lactylation. Nucleoporin 153 (NUP153) showed increased lactylation after aniline treatment. LDHA manipulation altered lactate abundance and the NUP153-associated Pan-Kla signal, and pharmacological activation of PPARγ partially restored lipid-metabolism markers. L-threonine supplementation partially restored EGR1/LDHA-associated responses, reduced lactate-related metabolic signals, and alleviated metabolic injury. These findings implicate LDHA-associated lactate accumulation and protein lactylation in aniline-induced hepatic metabolic dysfunction under the tested exposure conditions.

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