Celastrol’s covalent strike on HK2: Breaking a metabolic–epigenetic circuit to impede bladder cancer

This study investigated how the natural compound celastrol (CEL) impedes bladder cancer (BLCA) progression by irreversibly occupying the ATP-binding pocket of hexokinase 2 (HK2). CEL binds directly to the ATP cleft of HK2, permanently inactivating its enzymatic function and consequently suppressing glycolytic flux and lactate output in tumor cells. The diminished availability of lactate leads to reduced histone lactylation-a recently recognized epigenetic mark-which in turn downregulates the expression of the RNA methyltransferase METTL3 and decreases the global N⁶-methyladenosine (m⁶A) abundance. Importantly, we revealed a self-reinforcing circuit linking HK2‑driven glycolysis, histone lactylation, and METTL3‑dependent m⁶A deposition that fuels malignant growth. By stably engaging the ATP-binding pocket of HK2, CEL dismantles this metabolic-epigenetic feed‑forward loop, a mechanism that was substantiated through in vitro and in vivo assays and an analysis of clinical samples. Collectively, these results define a pivotal metabolic-epigenetic axis in BLCA and identify CEL as an agent that concurrently blocks energy production and post-transcriptional regulation. The results of the present study underscore the promise of irreversible HK2 blockade as a novel therapeutic avenue for managing BLCA.