PKM2 inhibitor suppresses kidney fibrogenesis by disrupting YAP-TEAD-CCN2 transcriptional signaling following ischemia–reperfusion injury

TL;DR

This study shows that inhibiting PKM2 can reduce kidney fibrosis by blocking a specific signaling pathway, offering a potential new treatment for chronic kidney disease.

Contribution

The study identifies PKM2 as a transcriptional cofactor promoting kidney fibrosis and demonstrates its inhibition as a therapeutic strategy.

Findings

Pharmacological inhibition of PKM2 reduces renal atrophy and fibrotic markers in mouse models.

PKM2 interacts with YAP and β-catenin to regulate fibrosis-related gene expression.

Compound 3k effectively inhibits PKM2 and YAP-TEAD signaling even when administered late.

Abstract

Fibrosis progressively impairs organ function and drives the progression of chronic kidney disease (CKD), for which effective targeted therapies are lacking. Although metabolic reprogramming toward glycolysis promotes fibrosis, the molecular link between metabolic shifts and transcriptional control in CKD and its therapeutic potential has not yet been established. In this study, we demonstrate that pyruvate kinase M2 (PKM2) orchestrates renal fibrosis via nuclear translocation and interaction with the Yes-associated protein (YAP) and beta-catenin (β-catenin) transcriptional networks. Using unilateral ischemia–reperfusion injury mouse models and human renal tubular epithelial cells, we revealed that pharmacological inhibition and genetic knockdown of PKM2 markedly attenuate renal atrophy and the expression of fibrotic markers, including cellular communication network factor 2. Mechanistically, compound 3k inhibited the nuclear translocation of PKM2 and YAP, thereby suppressing TEA domain transcription factor (TEAD)-mediated communication network factor 2 transcription. Similarly, siRNA-mediated silencing of PKM2 further confirmed the inhibition of YAP-TEAD signaling. Furthermore, co-immunoprecipitation confirmed that PKM2 forms complexes with YAP and β-catenin, integrating metabolic and transcriptional regulation. Our findings provide direct evidence that PKM2 promotes fibrosis in CKD through its role as a transcriptional cofactor rather than via its enzymatic activity. Notably, PKM2 inhibition by compound 3k remained effective even with delayed intervention, suggesting clinical translatability. Overall, these findings highlight PKM2 as a key integrator of metabolic and transcriptional reprogramming in kidney fibrosis and provide crucial preclinical evidence supporting PKM2-targeted strategies in CKD.

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