Background: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease, and its progression is closely associated with metabolic stress and epigenetic dysregulation under high-glucose conditions. Emerging evidence suggests that histone lactylation may play a pivotal role in gene transcription regulation during renal injury. This study aimed to elucidate the underlying mechanism by which histone lactylation of YTHDF2 exacerbates renal injury in a high-glucose environment, specifically through the enhancement of N6-methyladenosine (m6A) modification of growth differentiation factor 15 (GDF15), using both in vivo and in vitro models.

Methods: Histone lactylation and its role in renal injury were investigated in mouse renal tissues and in HK-2 tubular epithelial cells exposed to high glucose. Experimental approaches included immunofluorescence, ELISA, and immunoblotting. Autophagy and pyroptosis pathways were analyzed using markers such as LC3 and NLRP3. The histone lactylation on YTHDF2 transcription was evaluated using RT-qPCR, Chromatin immunoprecipitation (ChIP)-qPCR, and immunoblotting. Additionally, the impact of YTHDF2 on the m6A modification of GDF15 and its contribution to renal injury were examined using PAR-CLIP and MeRIP assays.

Results: Histone lactylation levels were significantly elevated in DN renal tissues and in HK2 cells exposed to high glucose (p < 0.01). Inhibition of histone lactylation alleviated high glucose-induced renal injury (p < 0.01). Interestingly, lactylation inhibition promoted autophagy while suppressing pyroptosis in both in vivo and in vitro DN models (p < 0.05). Histone acylation enhanced the transcriptional activation of YTHDF2, and YTHDF2 overexpression further aggravated renal injury (p < 0.05). Mechanistically, YTHDF2 facilitated the m6A modification of GDF15, leading to mRNA degradation and subsequent exacerbation of renal damage (p < 0.05).

Conclusion: Histone lactylation promotes the transcriptional activation of YTHDF2, which aggravates high glucose-induced renal injury by enhancing m6A-mediated degradation of GDF15 mRNA. Targeting the YTHDF2-GDF15 axis may represent a promising therapeutic strategy for DN.