Fuente: PubMed "nature biotechnology" Int J Obes (Lond). 2026 Jul 10. doi: 10.1038/s41366-026-02157-5. Online ahead of print.ABSTRACTBACKGROUND: Obesity is a serious multifactorial disease that involves epigenetic mechanisms like DNA methylation. Tyrosine kinase inhibitors (TKIs), originally synthesized and approved for cancer therapy, have recently been linked to the regulation of obesity. We evaluated whether LPM4870108, a small-molecule TKI with antitumor efficacy, contributes to obesity via DNA methylation.METHODS: LPM4870108 (TKI) was administered orally to rats at 0, 1.25, 2.5, or 5.0 mg/kg (for 28 days, twice daily). Body weights (BWs) and food intake were recorded daily. After 28 days of administration, ventromedial hypothalamus (VMH) tissues were collected for whole-genome transcriptomic and methylation sequencing to identify candidate genes. The mRNA expression and promoter methylation of candidate genes were analyzed by real-time RT-PCR and pyrosequencing, respectively. Protein levels of DNA methyltransferases (DNMTs) were determined by Western blot.RESULTS: LPM4870108 treatment substantially increased food intake and BW. Whole-genome transcriptomic and methylation profiling identified 415 differentially expressed genes (DEGs) and 124,935 differentially methylated regions (DMRs) within the VMH of LPM4870108-treated rats. The transcriptomic results were combined with whole-genome methylation sequencing data, followed by further verification via RT-PCR and pyrosequencing, through which the obesity-related candidate gene arginine vasopressin (AVP) was identified. Among all DEGs, AVP showed the most prominent change, with a negative association between its promoter methylation and mRNA expression level. Reduced protein expression of DNA methyltransferase 3A (DNMT3A) in the VMH was also detected in LPM4870108-treated rats.CONCLUSIONS: These findings indicate that LPM4870108-stimulated hyperphagia and weight gain were associated with DNA hypomethylation and concomitant upregulation of the AVP gene. LPM4870108, tyrosine kinase inhibitors; VMH, ventromedial hypothalamus; RRBS, reduced representation bisulfite sequencing; AVP, arginine vasopressin; DNMT, DNA methyltransferases.PMID:42432101 | DOI:10.1038/s41366-026-02157-5