Sepsis-induced myocardial dysfunction (SIMD) is a common, life-threatening complication of sepsis driven by overlapping disturbances in inflammation, oxidative stress, metabolism, and mitochondrial function. Recent research highlights post-translational modifications (PTMs) as dynamic regulators of protein behavior—altering activity, stability, localization, and signaling—and positions PTMs as central modulators of the pathophysiology that underlies SIMD.
This review synthesizes evidence from original studies and authoritative reviews, predominantly published within the past decade, to summarize how major PTMs influence the cellular and molecular processes that contribute to myocardial injury during sepsis.
Current evidence identifies several PTMs as important in SIMD pathobiology. These include phosphorylation, acetylation, ubiquitination, protein methylation, ADP-ribosylation, and palmitoylation. Each modification type exerts regulatory effects on proteins that participate in inflammation, oxidative stress responses, mitochondrial homeostasis, metabolic pathways, programmed cell death, and contractile machinery.
The review emphasizes that multiple PTMs operate across the same pathways and that their combined actions influence the net cellular response to septic insults in the myocardium.
PTMs modulate signaling cascades that underlie myocardial inflammation and oxidative stress—two central drivers of SIMD. By altering enzyme activity, protein–protein interactions, and subcellular localization, PTMs can amplify or attenuate inflammatory signaling and the production or detoxification of reactive oxygen species.
The collective impact of PTM-regulated changes in inflammatory mediators and antioxidant defenses contributes to myocardial cell injury and dysfunction in sepsis.
Mitochondrial disturbance and metabolic reprogramming are key features of SIMD. PTMs influence mitochondrial proteins and metabolic enzymes, which in turn affects energy production, oxidative phosphorylation, and substrate utilization in cardiac cells exposed to septic conditions.
Through modulation of mitochondrial function and metabolic pathways, PTMs can promote energetic failure, increase oxidative damage, and predispose cardiomyocytes to apoptosis or other forms of cell death that impair contractile performance.
An important theme is the existence of crosstalk among different PTMs. Interactions between phosphorylation, acetylation, ubiquitination, methylation, ADP-ribosylation, and palmitoylation create an integrated signaling network rather than isolated modification events. This crosstalk allows coordinated regulation of downstream effectors but also increases mechanistic complexity, making the net functional consequences of modifying one PTM dependent on the status of others.
A systematic, network-level characterization of these interactions is necessary to understand how combined PTM patterns drive SIMD pathogenesis and to identify rational points for therapeutic intervention.
The review notes that upstream epigenetic mechanisms can influence PTM-mediated signaling. Specifically, DNA methylation and N6-methyladenosine (m6A) RNA modification are highlighted as regulators that can modulate the expression or activity of enzymes responsible for installing or removing PTMs. Thus, epigenetic changes can shape PTM landscapes and downstream myocardial responses during sepsis.
Experimental studies cited in the review indicate that pharmacological modulation of PTM-regulated pathways can attenuate myocardial injury in preclinical models. Interventions targeting enzymes or pathways influenced by PTMs have shown protective effects in animal studies and cultured cells, supporting the concept that PTMs are actionable molecular targets in SIMD.
However, the review underscores that most mechanistic and therapeutic data originate from nonhuman models; robust validation in human septic myocardium remains limited.
A recurring limitation identified is the translational gap between mechanistic findings in animals or cell systems and demonstrated relevance in human disease. The review calls for systematic characterization of PTM crosstalk and rigorous human translational studies to confirm which PTM-related mechanisms are operative in clinical SIMD and which targets are amenable to safe and effective modulation.
Without such human-focused validation, PTM-directed strategies cannot yet be recommended for clinical practice.
PTMs represent promising mechanistic and therapeutic targets in SIMD because they regulate multiple pathophysiological domains central to septic myocardial injury. Future priorities include comprehensive mapping of PTM networks in septic human myocardium, elucidation of clinically relevant PTM crosstalk, and well-designed translational studies to test PTM-targeted interventions identified in preclinical work.
Only through systematic, human-centered research can the potential for PTM-based therapies be translated into clinically useful strategies for preventing or treating sepsis-induced myocardial dysfunction.