The correlation coefficient between HMGB1 as the independent variable produced a significant negative (ecological) correlation with HR, EF% and TLR4 at p < 0.05.<h4>Conclusion</h4>The ability of HMGB1 in downregulating inflammation or the direct inhibition of HMGB1 using small molecules or blocking of HMGB1/TLR4/NF-kB signalling pathway could be a novel potential mechanism to resolving DCM which requires further investigations.<h4>Systematic review registration</h4>https://www.crd.york.ac.uk/prospero/, identifier CRD42024597641. Here, HMGB1 is linked to familial dilated cardiomyopathy.