Sodium Lactate Attenuates Paraquat-Induced Early Profibrotic Remodeling: Association with GPR81/AMPK Modulation

Objective: Early profibrotic remodeling following acute lung injury is a major contributor to long-term morbidity in survivors of paraquat. Although metabolic reprogramming and lactate accumulation have been implicated in fibrotic processes, the regulatory role of lactate signaling in paraquat-induced fibrogenesis remains poorly understood. In this study, we hypothesized that exogenous sodium lactate attenuates paraquat-induced early profibrotic remodeling by modulating the lactate–GPR81–AMPK signaling axis, thereby suppressing inflammation and epithelial–mesenchymal transition (EMT). Methods: We established a paraquat (PQ)-induced lung injury/fibrosis model in C57BL/6 mice, dividing animals into four groups (control, PQ, sodium lactate, PQ + sodium lactate; n = 6 per group). At 48 h post intervention, lung tissues and plasma were collected for histological analysis (H&E, Masson), Ashcroft scoring, lactate quantification, and gene/protein expression assays (qRT-PCR, Western blot) targeting fibrosis, inflammatory, and signaling pathway markers (COL1A1, Vimentin, α-SMA, LDHA, GPR81, and AMPK). Parallel in vitro experiments used A549 epithelial cells treated with PQ ± sodium lactate to assess inflammatory cytokine release, EMT/fibrosis marker changes, and GPR81/AMPK pathway activity. Group comparisons utilized t-tests or one-way ANOVA, with p < 0.05 defined as statistically significant. Result: In vivo, sodium lactate significantly mitigated PQ-induced structural lung injury and interstitial fibrosis, as shown by lower Ashcroft scores and reduced fibrotic area on Masson staining. It suppressed both mRNA and protein expression of COL1A1, Vimentin, α-SMA, and LDHA. Inflammatory mediators IL-6, IL-1β, and TNF-α were decreased in the sodium lactate group. Mechanistically, PQ exposure upregulated GPR81 and downregulated AMPK expression; sodium lactate partially reversed these changes. In vitro, sodium lactate attenuated PQ-induced EMT and inflammatory responses in A549 cells, accompanied by restoration of GPR81/AMPK signaling. Conclusions: Our findings suggest that sodium lactate may serve as a modulator of the lactate–GPR81–AMPK axis to dampen inflammation and EMT, thereby impeding the progression of paraquat-induced early profibrotic remodeling. This work provides mechanistic insight and supports sodium lactate as a potential therapeutic strategy to prevent fibrotic paraquat-induced remodeling.