Sepsis can weaken the heart at the very moment the body most needs strong circulation, yet the biological chain driving this damage remains difficult to interrupt. A preclinical study now shows that 4-phenylbutyric acid (4-PBA) can ease sepsis-induced myocardial dysfunction (SIMD) by restoring the balance between mitochondrial division and fusion in heart cells. Rather than acting only on inflammation, the compound reduced excessive contacts between mitochondria and the endoplasmic reticulum, lowered lactate production and limited lactylation of actin-related protein 2/3 complex subunit 1B (ARPC1B). By targeting hexokinase 2 (HK2), 4-PBA helped preserve mitochondrial structure, energy production and cardiac contraction, revealing a connected metabolic and organelle-based pathway that may offer new therapeutic targets.
Sepsis triggers widespread inflammation, circulatory failure and metabolic stress, and cardiac dysfunction is a common complication associated with sharply poorer outcomes. Current supportive treatments can stabilize blood pressure or improve contraction, but they do not directly correct the cellular mechanisms that leave cardiomyocytes energy-starved and structurally damaged. Mitochondria continuously divide and fuse to maintain quality and function, while the endoplasmic reticulum can wrap around them at specialized contact sites that help initiate fission. Excessive contact formation, disturbed glycolysis and lactate-driven protein modification may therefore converge on the same injury process. Based on these challenges, in-depth research is needed to determine how metabolic stress reshapes organelle contacts and mitochondrial dynamics during sepsis.
Researchers from the State Key Laboratory of Trauma and Chemical Poisoning and the Department of Shock and Transfusion at Daping Hospital, Army Medical University, together with the Department of Gynecologic Oncology at West China Second University Hospital, Sichuan University, reported (DOI: 10.1093/burnst/tkag039) the study online on June 3, 2026, in Burns & Trauma . Published as an accepted manuscript, the work combines patient-derived transcriptomic evidence with animal and cellular experiments to examine how 4-phenylbutyric acid (4-PBA) protects the septic heart through a pathway linking glycolysis, lactate-dependent protein modification, mitochondria-associated endoplasmic reticulum membranes (MAMs) and mitochondrial dynamics.
The team first analyzed public blood and myocardial transcriptomic datasets and single-nucleus heart profiles, finding that endoplasmic reticulum stress rose as cardiomyocyte contraction programs declined. They then used cecal ligation and puncture (CLP) models in mice and rats, septic-serum-treated heart cells, live-cell imaging, electron microscopy, metabolic and protein profiling, molecular docking and targeted mutations. Among three endoplasmic reticulum stress inhibitors, 4-PBA at 5 milligrams per kilogram produced the strongest cardiac protection, improving left ventricular ejection fraction, left ventricular fractional shortening, cardiac output, blood pressure and survival. In cultured cells, it preserved mitochondrial membrane potential, oxygen consumption and adenosine triphosphate (ATP) production while reducing reactive oxygen species (ROS). Sepsis increased MAM formation more than threefold; 4-PBA cut the contact-area signal by 36.1% and restored a healthier balance of mitochondrial fission and fusion. Mechanistically, 4-PBA bound the K621 and K624 catalytic residues of HK2, suppressing glycolysis and lactate accumulation. Lower lactate reduced lactylation of actin-related protein 2/3 complex subunit 1B (ARPC1B) at lysine 308, limiting actin-driven MAM formation. Mutation experiments supported this sequence: a lactylation-mimicking ARPC1B variant promoted mitochondrial fragmentation, whereas a non-lactylated mimic improved mitochondrial and cardiac function.
The authors said the findings reveal a chain of events that connects metabolic overload to physical changes inside heart cells. In their interpretation, 4-PBA does more than reduce endoplasmic reticulum stress: it interrupts hexokinase 2 (HK2)-driven lactate production, prevents excessive modification of ARPC1B and stops mitochondria from being repeatedly pinched into dysfunctional fragments. They said this integrated mechanism helps explain why mitochondrial energy failure and impaired contraction develop together during sepsis. The study therefore shifts attention from isolated inflammatory signals toward the coordinated control of metabolism, cytoskeletal remodeling and organelle contacts, while identifying several points that could be tested as therapeutic targets.
The results support 4-PBA, HK2, ARPC1B lactylation and MAM formation as candidates for future drug-development studies in septic cardiac injury. Because 4-PBA has shown biological activity in other disease models, its newly described mechanism could also guide the design of more selective compounds that preserve mitochondrial dynamics without broadly altering cellular stress responses. However, the evidence remains preclinical. The experiments relied on rodent sepsis models and rat-derived cells, and treatment effects were mainly assessed within 12 to 24 hours. Human immune responses, drug metabolism and cardiac physiology may differ substantially. Longer studies must define dose limits, delayed effects, organ toxicity and treatment timing before clinical trials can determine whether this pathway can safely improve outcomes in patients.
