Inhibition of calpain-mediated HMGB1 alleviates cardiac inflammation and dysfunction induced by ultra-processed foods

Claire Ross; Sanskruti Ravindra Gare; Nasser H. Alatawi; Oveena Fonseka; Xinyi Chen; Jiayan Zhang; Yihua Han; Andrea Ruiz-Velasco; Riham R.E. Abouleisa; Yingjuan Liu; Xiangjun Zhao; Han Xiao; Bernard Keavney; Gareth J. Howell; Tao Wang; Tamer M.A. Mohamed; Elizabeth J. Cartwright; Wei Liu

doi:10.1172/jci.insight.199622

Inhibition of calpain-mediated HMGB1 alleviates cardiac inflammation and dysfunction induced by ultra-processed foods

Claire Ross,¹ Sanskruti Ravindra Gare,¹ Nasser H. Alatawi,¹ Oveena Fonseka,¹ Xinyi Chen,¹ Jiayan Zhang,¹ Yihua Han,¹ Andrea Ruiz-Velasco,¹ Riham R.E. Abouleisa,² Yingjuan Liu,¹ Xiangjun Zhao,¹ Han Xiao,³ Bernard Keavney,¹ Gareth J. Howell,¹ Tao Wang,¹ Tamer M.A. Mohamed,¹ Elizabeth J. Cartwright,¹ and Wei Liu¹

Published April 22, 2026 - More info

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Abstract

Increased consumption of ultra-processed foods (UPFs) is a risk factor for metabolic disorders-associated heart failure (HF). Here, we demonstrate that UPF-induced calpain-1 aggravated oxidative stress, thereby increasing high mobility group box 1 (HMGB1)-mediated myocardial inflammation, which contributes to cardiac dysfunction. After illustrating the dysregulated inflammatory pathways in human and murine hearts upon metabolic stress, we revealed an increase in calpain-1 alongside profound oxidative stress and inflammation in the failing myocardium. Mechanistically, in neonatal rat cardiomyocytes (NRCMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), HMGB1 was upregulated by calpain-1 and reactive oxygen species (ROS) upon stress of saturated and trans fatty acids (FA). Consequently, HMGB1 promoted a pro-inflammatory response in macrophages. On the contrary, inhibition of calpain or ROS efficiently repressed HMGB1 in cardiomyocytes. Therapeutically, either recombinant adeno-associated virus 9 (AAV9) delivered inhibitor of calpain-1 or its pharmacological inhibitor attenuated ROS and HMGB1-induced inflammation in the myocardium and mitigated HF in both male and female mice fed with an ultra-processed diet (UPD). Collectively, we have demonstrated the effects of suppressing calpain-1 and oxidative stress on alleviating myocardial inflammation via blockage of HMGB1 and cardiac dysfunction. The results provide a promising therapeutic strategy for preventing or treating HF in metabolic disorders.

Inhibition of calpain-mediated HMGB1 alleviates cardiac inflammation and dysfunction induced by ultra-processed foods

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Inhibition of calpain-mediated HMGB1 alleviates cardiac inflammation and dysfunction induced by ultra-processed foods

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