RILPL2 suppresses metabolic reprogramming and progression of cervical cancer by attenuating LDHA protein stability and inhibiting H3K18 lactylation.

Cervical cancer (CC) is a prevalent malignancy among women worldwide with considerable incidence and mortality. Recent studies have suggested that the Rab-interacting lysosomal protein-like 2 (RILPL2) acts as a tumor suppressor and plays an inhibitory role in multiple human cancers. However, the potential effect of RILPL2 in CC remains unclear. In our investigation, we found that RILPL2 was downregulated in CC samples and was associated with a favorable outcome. Further findings indicated the interaction between RILPL2 and lactate dehydrogenase A (LDHA), a crucial player regulating glycolysis. Mechanistically, RILPL2 reduced LDHA stability by recruiting TRIM21 to facilitate K48-linked ubiquitination chains of LDHA and promoting LDHA degradation, thereby blocking glycolytic reprogramming and, in turn, inhibiting CC progression and development. Moreover, RILPL2-mediated inhibition of the glycolytic pathway could restrain lactate production, which abolished H3K18 lactylation to induce the downregulation of SOX9 and SMYD2. Consequently, our results suggested that RILPL2 may serve as a potential therapeutic target for the treatment of CC.