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Autophagy is extensively implicated in adaptive mechanisms for cell survival. Interleukin\u201033 (IL\u201033) is known to be a potent cardiac protector, but its roles in DCM, ER stress, and autophagy are currently unknown. We aimed to explore the effects of IL\u201033 on DCM and characterize the roles that ER stress and autophagy play in DCM. The effects of IL\u201033 on DCM, ER stress, and autophagy were characterized both in db\/db mice and in palmitic acid (PA)\u2010treated cardiomyocytes. The manipulators of ER stress and autophagy were used to clarify their roles in DCM remittance conferred by IL\u201033. Gene expression analysis was used to identify IL\u201033\u2010dependent regulators of ER stress and autophagy. Both db\/db mice and PA\u2010treated cells presented with enhanced levels of ER stress, apoptosis, and lipid deposition, as well as impaired autophagy, all of which could be reversed by IL\u201033. Treatment with IL\u201033 improved the cardiac diastolic function of diabetic mice. Nonselective autophagy inhibitors, such as 3\u2010methyladenine (3\u2010MA) or wortmannin, abolished the protective effects of IL\u201033, resulting in an increase in both ER stress and apoptosis. Strikingly, insulin\u2010like growth factor\u2010binding protein 3 (IGFBP3) was identified as the gene most significantly differentially expressed between IL\u201033 and control groups. Knockdown of IGFBP3 expression, similar to the effect of nonselective autophagy inhibitors, resulted in high levels of ER stress, impaired autophagy, and apoptosis that were not rescued upon treatment with IL\u201033. IL\u201033 abates DCM by alleviating ER stress and promoting autophagy. IGFBP3 is essential for IL\u201033\u2010induced ER stress resolution and autophagic enhancement during DCM.<\/jats:p>","DOI":"10.1002\/jcp.30158","type":"journal-article","created":{"date-parts":[[2020,11,13]],"date-time":"2020-11-13T03:52:33Z","timestamp":1605239553000},"page":"4403-4419","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Interleukin\u201033 alleviates diabetic cardiomyopathy through regulation of endoplasmic reticulum stress and autophagy via insulin\u2010like growth factor\u2010binding protein 3"],"prefix":"10.1002","volume":"236","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6943-2763","authenticated-orcid":false,"given":"Mao\u2010Xiong","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Cardiology, Sun Yat\u2010sen Memorial Hospital Sun Yat\u2010sen University  Guangzhou Guangdong China"},{"name":"Laboratory of Cardiac Electrophysiology and Arrhythmia in Guangdong 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