YTHDC1 lactylation regulates its phase separation to enhance target mRNA stability and promote RCC progression

The hypoxic and lactate-enriched microenvironment of renal cell carcinoma (RCC) provides favorable conditions for aberrant lysine lactylation (Kla). However, the functional role and mechanistic basis of Kla in RCC progression remain elusive. Here, we showed an elevated global Kla level in human RCC tissues and cells, which promoted RCC malignancy. Through lactylome analysis of human RCC cells under hypoxia-mimicking conditions, we found that the m6A reader YT521-B homology (YTH) domain-containing 1 (YTHDC1) is modified by Kla at K82. YTHDC1^K82la, mediated by p300 under hypoxia, promotes RCC malignancy both in vitro and in vivo. Mechanistically, YTHDC1^K82la increases YTHDC1 phase separation, leading to the expansion of nuclear condensates and safeguarding oncogenic transcripts BCL2 and E2F2 from degradation by the poly A-tail exosome targeting (PAXT)-exosome complex in human RCC cells. Our results demonstrated that augmented Kla advances RCC progression by modulating phase separation and thereby regulating the stability of YTHDC1 target genes.