靶向抑制KDM1A调控肿瘤恶病质骨骼肌降解的作用机制研究OA

Objective:To explore the regulatory role and molecular mechanism of Histone lysine-specific demethylase 1A(KDM1A)in skeletal muscle wasting during cancer cachexia.Methods:Cancer cachexia mouse models and C2C12 myotube mod-els were established and randomly divided into 4 groups:NC,NC+KDM1Ai,CC,CC+KDM1Ai.RNA sequencing and bioinfor-matics analysis were performed to identify the key regulatory functions of KDM1A in skeletal muscle.qPCR,Western blot and im-munofluorescence were used to detect the expression levels of KDM1A,MuRF-1,and Atrogin1.Immunofluorescence and H&E staining were employed to evaluate the cross-sectional area(CSA)of skeletal muscle fibers and myotube diameter in mice.West-ern blot was conducted to analyze the expression of STAT3,phosphorylated STAT3(pYSTAT3),and histone methylation marks(H3K4me1,H3K4me2,H3K9me1,H3K9me2)to elucidate the regulatory mechanism of KDM1A.Results:Transcrip-tomic data analysis revealed that KDM1A plays a specific role in muscle wasting during cancer cachexia.Both in vivo and in vitro cancer cachexia models,the mRNA and protein expression levels of KDM1A,MuRF-1,and Atrogin1 were significantly upregu-lated(P<0.05).Inhibition of KDM1A markedly improved cachexia-related parameters in tumor-bearing mice,including the rate of body weight loss,lean mass,hindlimb muscle weight,quadriceps weight,heart weight,and grip strength(P<0.05).In both animal and cellular experiments,KDM1A inhibition significantly increased the CSA of muscle fibers and myotube diameter,while downregulating the mRNA and protein levels of MuRF-1 and Atrogin1(P<0.05).Compared to the cachexia group,the inhibitor-treated cachexia group exhibited upregulated histone methylation levels(H3K4me1,H3K9me1,and H3K9me2),indicating im-proved histone methylation.KDM1A inhibition significantly reduced phosphorylated STAT3 levels(P<0.05),suggesting sup-pression of the STAT3 signaling pathway.Conclusion:KDM1A is upregulated during cancer cachexia and promotes muscle atro-phy.Inhibition of KDM1A exerts a protective effect against muscle wasting in cancer cachexia,potentially through restoring his-tone methylation and inhibiting the STAT3 signaling pathway.