Inhibition of Calpain-Mediated HMGB1 Alleviates Cardiac Inflammation and Dysfunction Induced by Ultra-Processed Foods

Authors

• Claire Ross
• Sanskruti Ravindra Gare
• Nasser Ho Alatawi
• Oveena Fonseka
• Xinyi Chen
• Jiayan Zhang
• Yihua Han
• Andrea Ruiz-Velasco
• Riham Re Abouleisa
• Yingjuan Liu
• Xiangjun Zhao
• Han Xiao
• Bernard D Keavney
• Gareth J Howell
• Tao Wang
• Tamer Ma Mohamed
• Elizabeth J Cartwright
• Wei Liu

Language

English

Publication Date

6-8-2026

Journal

JCI Insight

DOI

10.1172/jci.insight.199622

PMID

42018559

PMCID

PMC13313562

PubMedCentral® Posted Date

4-9-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Increased consumption of ultra-processed foods (UPFs) is a risk factor for metabolic disorder-associated heart failure (HF). Here, we demonstrate that UPF-induced calpain-1 aggravated oxidative stress, thereby increasing high mobility group box 1-mediated (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 and human induced pluripotent stem cell-derived cardiomyocytes, HMGB1 was upregulated by calpain-1 and reactive oxygen species (ROS) upon stress of saturated and trans fatty acids. Consequently, HMGB1 promoted a proinflammatory response in macrophages. In contrast, inhibition of calpain or ROS efficiently repressed HMGB1 in cardiomyocytes. Therapeutically, either recombinant adeno-associated virus 9-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. 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.

Keywords

Animals, Calpain, HMGB1 Protein, Mice, Humans, Male, Myocytes, Cardiac, Oxidative Stress, Rats, Female, Reactive Oxygen Species, Heart Failure, Myocardium, Inflammation, Mice, Inbred C57BL, Food, Processed, Myocarditis, Fast Foods, Cardiology, Inflammation, Metabolism, Diabetes, Heart failure

Published Open-Access

yes

Recommended Citation

Ross, Claire; Gare, Sanskruti Ravindra; Alatawi, Nasser Ho; et al., "Inhibition of Calpain-Mediated HMGB1 Alleviates Cardiac Inflammation and Dysfunction Induced by Ultra-Processed Foods" (2026). Faculty, Staff and Students Publications. 8623.
https://digitalcommons.library.tmc.edu/baylor_docs/8623