Sugar Tag on ASGR1 Protein Curbs Deadly Heart Damage in Sepsis

Sepsis-induced cardiomyopathy, a heart-weakening complication of severe infection that contributes to high mortality in critically ill patients, has gained a new molecular lead. A study published in Cell Biology and Toxicology reports that a sugar-based modification of the protein asialoglycoprotein receptor 1, known as ASGR1, can lessen septic cardiac injury by restraining a form of inflammatory cell death called PANoptosis, which is driven in cardiomyocytes by the protein ZBP1.

The research combined several lines of evidence. The team used samples from patients with sepsis-induced cardiomyopathy for preliminary verification, then turned to mouse models, including global and cardiomyocyte-specific ASGR1 knockout animals, as well as ASGR1-knockout cardiomyocytes and rescue experiments, to define the protein’s role. Proteomics, RNA sequencing, bioinformatic analysis, molecular docking and dynamics simulations were used to pinpoint the O-GlcNAcylation site on ASGR1 and identify its binding partners.

The central finding is a post-translational tug-of-war. In cells exposed to LPS, a bacterial endotoxin used to model sepsis, levels of the enzyme OGT fall. OGT is what attaches O-GlcNAc, a single sugar modification, to ASGR1. When that sugar tag is lost, ASGR1 separates from AMFR, an E3 ligase that normally tags the receptor for K48-linked proteasomal degradation. Freed from this destruction route, ASGR1 accumulates to pathological levels.

That accumulation matters because stabilized ASGR1 interacts with ZBP1, initiating PANoptosis in cardiomyocytes and worsening septic cardiac dysfunction. Conversely, the study found that either deleting ASGR1 or elevating its O-GlcNAcylation reduced myocardial injury and improved survival in septic mice. The authors describe the effect as cell-type-specific: ASGR1 acts as a pro-PANoptotic driver within cardiomyocytes through a cardiac OGT- and AMFR-governed signaling pathway, distinct from inflammatory immune-cell cascades.

This cardiomyocyte-autonomous mechanism marks a departure from the same group’s earlier work, which characterized ASGR1-triggered neutrophil ferroptosis and NETosis. In the new study, the O-GlcNAcylation and ubiquitination crosstalk operates inside heart muscle cells themselves, separate from the immune inflammatory programs previously described.

The authors frame the work as answering two questions in sepsis-induced cardiomyopathy: the upstream cascade responsible for ASGR1 accumulation, and the ASGR1-ZBP1 signaling axis that drives myocardial PANoptosis. They propose the OGT-ASGR1-ZBP1 regulatory cascade as a promising therapeutic target, potentially addressable through modulation of post-translational modifications.

Important caveats apply. The human component served as preliminary verification only, and the mechanistic conclusions rest on mouse models, engineered cardiomyocytes and cell-based rescue assays rather than tested therapies in patients. The article is also being shared early as a peer-reviewed, accepted manuscript that remains subject to further editing before the final version of record. No clinical treatment based on these findings yet exists, and translating O-GlcNAcylation modulation into a safe intervention would require substantial further work.

By showing that a single sugar modification can redirect a receptor protein between degradation and a death-signaling interaction with ZBP1, the work illustrates how post-translational modification crosstalk can govern organ-level outcomes in sepsis, and it identifies ASGR1, for the first time according to the authors, as an essential driver of cardiomyocyte PANoptosis in septic cardiac dysfunction.

Subject of Research: O-GlcNAcylation of ASGR1 regulating ZBP1-mediated PANoptosis in sepsis-induced cardiomyopathy

Article Title: O-GlcNAcylation of ASGR1 alleviates sepsis-induced cardiomyopathy via repressing ZBP1-mediated PANoptosis

Article References: Shi, R., Wang, F., Wang, H., Wu, H., Lun, J., Bai, C., Li, C., Chen, A. F., & Yang, W. (2026). O-GlcNAcylation of ASGR1 alleviates sepsis-induced cardiomyopathy via repressing ZBP1-mediated PANoptosis. Cell Biology and Toxicology. https://doi.org/10.1007/s10565-026-10280-2

Image Credits: AI Generated

DOI: 10.1007/s10565-026-10280-2

Keywords: sepsis-induced cardiomyopathy, ASGR1, O-GlcNAcylation, PANoptosis, ZBP1, OGT, AMFR, cardiomyocytes, post-translational modification, proteasomal degradation, sepsis, preclinical study