What question did this study set out to answer?

This research aims to elucidate the role of phosphofructokinase liver type (PFKL) lactylation in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD).

June 10, 2026

1336-OR: A Lactate-PFKL Lactylation Positive Circuit Promotes the Progression of MASLD

Puntos clave

This research aims to elucidate the role of phosphofructokinase liver type (PFKL) lactylation in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD).
Quantitative lactylome and proteomic analyses were performed in HFD-fed mice.
Human and mouse MASLD samples were analyzed for hepatic lactate levels and global Kla.
In vitro assays and metabolic phenotyping were used to assess PFKL lactylation and its effects.
Elevated hepatic lactate levels and global Kla were observed in MASLD patients and HFD/MCD-fed mice, correlating with disease severity.
Lactylation at lysine 677 enhanced PFKL's enzymatic activity and attenuated its degradation by TRIM25, leading to increased glycolytic flux.
Targeting PFKL lactylation through LDHA knockdown or pharmacological inhibition significantly improved MASLD progression.

Resumen

Introduction and Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health challenge with limited effective pharmacological therapies. Although lysine lactylation has emerged as an important regulator of metabolic homeostasis, whether lactylation of the key glycolytic enzyme phosphofructokinase liver type (PFKL) drives MASLD progression and the underlying mechanisms remain obscure. Methods: Quantitative lactylome and proteomic analyses were performed in HFD-fed mice. Hepatic lactate levels and global Kla were assessed in human and mouse MASLD samples. PFKL lactylation sites and enzymatic activity were analyzed in vitro assays. C57BL/6J mice were injected with AAV9-TBG-PFKL or AAV9-TBG-PFKL-K677R, followed by metabolic phenotyping. Mass spectrometry, co-IP, and ubiquitination assays were conducted to investigate the mechanisms of TRIM25-mediated PFKL degradation. Results: Hepatic lactate levels and global Kla were markedly elevated in patients with MASLD and in HFD- or MCD-fed mice, correlating with disease progression. Integrated lactylome and proteomic analyses identified PFKL as a key glycolytic regulator with increased expression and lactylation at lysine 677, dynamically regulated by PCAF. K677 lactylation enhanced PFKL enzymatic activity and protein stability by attenuating its interaction with the E3 ligase TRIM25, thereby preventing proteasomal degradation. Liver-specific expression of delactylation-mimic PFKL mutants conferred resistance to HFD-induced steatosis, insulin resistance, inflammation, and apoptosis. Elevated PFKL abundance promoted glycolytic flux and lactate accumulation, forming a positive feedback loop that sustained metabolic reprogramming and hepatic dysfunction. Disruption of this loop by LDHA knockdown or pharmacological inhibition effectively ameliorated MASLD progression. Conclusion: These findings reveal a lactylation-dependent mechanism driving MASLD progression and demonstrate that targeting PFKL lactylation may have therapeutic potential. Disclosure Y. Guo: None. H. Ren: None. G. Yuan: None. Funding National Natural Science Foundation of China (No. 82270855, No. 81974121, No. 82470867, No. 82470908 and No. 82100922)

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