Mechanisms of cardiomyopathy caused by obesity/hyperlipidemia are complicated.Obesity is usually associated with chronic low-grade inflammation and may lead to the onset and progression of myocardial fibrosis and remodeling.TLR4/MyD88 signaling pathway,as a key regulator of inflammation,plays an important role in the pathogenesis of obesity-induced cardiomyopathy.We previously demonstrated that LM9,a novel MyD88 inhibitor,attenuated inflammatory responses and fibrosis in obesity-induced cardiomyopathy by inhibiting the formation of TLR4/MyD88 complex.In this study,we investigated the protective effects of LM9 on obesity-induced cardiomyopathy in vitro and in vivo.We showed that LM9 (5,10 μM)significantly attenuates palmitic acid (PA)-induced inflammation in mouse peritoneal macrophages,evidenced by decreased expression of proinflammatory genes including TNF-α,IL-6,IL-1β,and ICAM-1.In cardiac-derived H9C2 cells,LM9 treatment suppressed PA-induced inflammation,lipid accumulation,and fibrotic responses.In addition,LM9 treatment also inhibited PA-activated TLR4/MyD88/NF-KB signaling pathway.We further revealed in HEK293 cells that LM9 treatment blocked the TLR4/MyD88 binding and MyD88 homodimer formation.In HFD-fed mice,administration of LM9 (5,10 mg/kg,ig,every other days for 8 weeks) dose-dependently alleviated inflammation and fibrosis in heart tissues and decreased serum lipid concentration.In conclusion,this study demonstrates that MyD88 inhibitor LM9 exerts protective effects against obesityinduced cardiomyopathy,suggesting LM9 to be a promising therapeutic candidate drug for the obesity-related cardiac complications.