The review, led by Leyu Ai, Huirong Wu, and colleagues, synthesizes a rapidly expanding body of evidence linking lactylation—a posttranslational modification first reported in 2019 by Yingming Zhao’s team—to regulated cell death (RCD), the family of programmed cell death pathways that includes apoptosis, ferroptosis, pyroptosis, PANoptosis, and NETosis. The central thesis is striking: when sepsis forces cells into a glycolytic metabolic state, the resulting lactate surge doesn’t just accumulate harmlessly. It is converted into lactyl-coenzyme A, which competes with acetyl-CoA for the same lysine residues on histones and nonhistone proteins, shifting the entire cellular acylation landscape toward lactylation and away from acetylation.

The mechanistic logic is elegant. Under healthy conditions, oxidative phosphorylation dominates glucose metabolism, generating abundant acetyl-CoA that drives lysine acetylation—the prevailing protein modification. Enzymes like the bifunctional acyltransferase AARS1 show a marked kinetic preference for acetyl-CoA: its Michaelis constant for acetyl-CoA is roughly 80 micromolar, compared with approximately 36 millimolar for lactyl-CoA, meaning the enzyme’s affinity for the acetyl substrate is orders of magnitude higher. But sepsis flips this balance. Hypoxia-inducible factor-1α upregulates lactate dehydrogenase A, while phosphorylation of the pyruvate dehydrogenase complex by PDK1/4 suppresses acetyl-CoA production. The resulting lactyl-CoA flood overwhelms the enzymatic threshold, allowing lactylation to seize dominance at shared modification sites.

Clinical data support this model. In a prospective cohort of 86 critically ill patients, serum lactate levels correlated positively with H3K18la—a histone lactylation mark at lysine 18 of histone H3—while H3K18ac levels fell. The H3K18la/ac ratio correlated with disease severity scores (APACHE II and SOFA), ICU length of stay, and duration of mechanical ventilation, suggesting the modification ratio itself may serve as a biomarker. Earlier work by Chu and colleagues found H3K18la highest in septic shock patients, correlating with inflammatory cytokines and macrophage polarization markers.

But the review’s most provocative contribution lies in mapping how these lactylation marks regulate cell death across organs. In sepsis-associated acute kidney injury—which affects up to 66 percent of septic patients—elevated H3K18la in renal tubular epithelial cells activates the RhoA/ROCK pathway and the Ezrin-MYD88-IRAK1-NF-κB inflammatory cascade, driving apoptosis. Nonhistone lactylation compounds the damage: excessive acetylation and inactivation of PDHA1 leads to lactate overproduction, which then induces lactylation of the mitochondrial fission protein Fis1 at lysine 20, triggering excessive mitochondrial fragmentation and tubular cell death.

In the lung, the picture is equally complex. Histone lactylation at H3K18 promotes alveolar epithelial apoptosis through at least two routes: it upregulates caspase-8, amplifying TNF-α-mediated pro-apoptotic signaling, and it drives EGR1 transcription and nuclear import, degrading the endothelial glycocalyx barrier. Meanwhile, lactylation regulates ferroptosis—iron-dependent lipid peroxidation-driven cell death—through multiple histone marks. H3K14la-mediated transcription upregulates the transferrin receptor TFRC and downregulates SLC40A1, creating iron overload that catalyzes reactive oxygen species via the Fenton reaction. H3K18la enriches at the promoters of ACSL4 and LC3, increasing polyunsaturated fatty acid content and promoting ferritinophagy. A protective feedback loop also exists: elevated H3K14la upregulates PARK7, which restores FADS1/2 enzyme activity and activates the NRF2/KEAP1 antioxidant pathway, suppressing ferroptosis.

Pyroptosis—inflammatory cell death executed by gasdermin pore formation—is another major target. Lactate entering macrophages via monocarboxylate transporter 1 is converted by AARS2 into lactyl-CoA, which mediates site-specific lactylation of NLRP3 at lysines 24 and 565. This modification promotes recruitment of the adaptor protein ASC and assembly of the NLRP3 inflammasome, activating caspase-1, cleaving GSDMD, and releasing mature IL-1β. In the brain, H3K18la upregulates YTHDF3, which stabilizes NLRP3 via the deubiquitinase USP9X, triggering microglial pyroptosis and neuroinflammation. In the kidney, H3K18la activates SPHK1, which phosphorylates and degrades SIRT1—disrupting both a delactylase feedback loop and mitochondrial homeostasis, creating a vicious cycle that amplifies pyroptotic injury.

Perhaps most intriguingly, the review documents bidirectional regulation. In macrophages, MCT1-dependent lactylation of ZBP1 disrupts its interaction with RIPK1/TRIF, promoting ZBP1 degradation and blocking ZBP1-mediated PANoptosis—thereby alleviating lung injury. Conversely, lactylation of CIRP promotes its nuclear-to-cytoplasmic translocation and exosomal release, which endothelial cells internalize via TLR4, stabilizing ZBP1 and enhancing PANoptosis in pulmonary epithelial cells. The same modification, acting on different substrates in different cell types, can either protect or destroy.

The authors also highlight autophagy as a newly identified lactylation target with bidirectional effects. During the hyperinflammatory phase, neutrophil-derived lactate drives H3K18la-mediated upregulation of ATG7, initiating nondegradative secretory autophagy that releases IL-1β and damages pulmonary endothelium. During the immunosuppressive phase, impaired glycolytic reprogramming reduces lactate production, lowering H3K18la and attenuating transcription of ATG5 and ATG16L1—crippling macrophage autophagic flux and bactericidal capacity, thereby promoting immune paralysis.

What emerges is a systems-level view: sepsis is not simply a cytokine storm or a circulatory collapse, but a global epigenetic reprogramming event in which metabolic flux dictates protein modification state, which in turn dictates cell fate. The review proposes that glucose metabolic flux distribution serves as a critical regulatory node—determining not only overall levels of acetylation and lactylation but also their spatiotemporal specificity. Multiorgan metabolomic studies showing enhanced metabolic coupling among abdominal organs, with decoupling of heart and skeletal muscle, suggest that systemic metabolic fluctuations may reshape lactylation profiles across organs simultaneously, mediating synchronous multiorgan injury before clinical dysfunction is detectable.

The clinical implications are substantial but preliminary. Existing lactylation research remains largely confined to single-center observational biomarker studies with small cohorts. No interventional clinical trials targeting the lactylation pathway have been reported. The enzyme kinetic data supporting the acylation competition model derive from in vitro purified systems; subcellular compartmentalization and cofactor microenvironments may reshape actual catalytic preferences in vivo. The lactate concentration threshold that drives modification preference shifts in bifunctional acyltransferases has not been systematically defined.

Artificial intelligence may accelerate the field. Deep learning tools like DeepKla can predict lysine lactylation sites with 93.22 percent accuracy. AI-driven multiomics frameworks have stratified patients into LDHA-high and LDHA-low subtypes with distinct prognoses, achieving sensitivity of 0.922 and precision of 0.955 in predicting lactylation-driven therapeutic responses. In pyroptosis research, a Transformer model trained on 40,000 protein interface data points generated the SK56 peptide, which specifically blocks the GSDMD-NT pore, delaying pyroptosis and alleviating inflammation. The review proposes an integrated multimodal model combining early sepsis warning, lactylation site identification, and RCD pathway intervention—a full-chain system spanning early detection through precision targeting.

Ultimately, the lactylation–RCD axis offers a fundamentally new therapeutic logic for sepsis. Rather than nonspecifically lowering systemic lactate, future strategies may target cell-selective metabolic intervention: modulating lactate synthesis or lactyl-CoA generation in specific cell subtypes to restore intracellular lactylation to physiological homeostatic range, thereby blocking RCD-mediated parenchymal organ injury while preserving myeloid pathogen clearance and immune defense. The field remains in its infancy, but the convergence of epigenetics, cell death biology, and artificial intelligence suggests that the humble lactate molecule—long dismissed as a metabolic dead end—may hold the key to rewriting the outcome of one of humanity’s deadliest syndromes.

Subject of Research: Sepsis, lactylation, regulated cell death, epigenetics, metabolic reprogramming

Article Title: Recent advances in research on the association between lactylation and regulated cell death in sepsis

Article References: Ai, L., Wu, H., Huang, W., Zhang, Y., Ma, Y., Wu, D., Chen, J., Fang, X., Liu, C., Wang, P., Cheng, W., Fu, H., Yin, W., Shen, K., & Li, J. (2026). Recent advances in research on the association between lactylation and regulated cell death in sepsis. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.10.026

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.10.026

Keywords: sepsis, lactylation, regulated cell death, apoptosis, ferroptosis, pyroptosis, PANoptosis, NETosis, epigenetics, metabolic reprogramming, H3K18la, lactate