Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, which is a life-threatening condition resulting from a dysregulated host response to infection. Pyroptosis, a pro-inflammatory mode of lytic cell death mediated by GSDMD (Gasdermin D), is involved in the pathogenesis of SAE. While autophagy has been extensively studied in SAE, the role of nuclear autophagy is not yet well understood. In this study, we aimed to investigate the involvement of pyroptosis and neural nuclear autophagy in the pathogenesis of SAE. We analyzed a CLP (cecal ligation and puncture)-induced SAE model in wild-type and GSDMD^−/− mice to gain insights into the underlying mechanisms. Here, we show that in sepsis, neural nuclear autophagy is extremely activated, and nuclear LaminB decreases and is accompanied by an increase in the ratio of LC3BII/I. These effects can be reversed in GSDMD^−/− mice. The behavioral outcomes of septic wild-type mice are impaired by the evidence from the novel object recognition test (NORT) and open field test (OFT), but are improved in septic GSDMD^−/− mice. In conclusion, our study demonstrates the activation of neural nuclear autophagy in SAE. The absence of GSDMD inhibits nuclear autophagy and improves the behavioral outcomes of SAE.

Sepsis-induced cardiomyopathy (SICM) is a frequent and clinically important complication of sepsis, characterized by acute and often reversible myocardial dysfunction and associated with poor outcomes in critically ill patients. Despite growing recognition of its clinical significance, effective mechanism-based therapies remain unavailable, largely because SICM is highly heterogeneous and driven by a complex interplay of inflammatory activation, endothelial and microcirculatory dysfunction, oxidative stress, mitochondrial injury, calcium-handling abnormalities, metabolic reprogramming, and dynamic cardiomyocyte adaptation. In recent years, increasing attention has been directed toward epigenetic regulation, as it provides a mechanistic framework linking septic stress to sustained transcriptional and post-transcriptional remodeling in the myocardium and its immune microenvironment. Numerous studies have therefore investigated epigenetic mechanisms in SICM, including DNA methylation, histone modifications, and non-coding RNA-mediated regulation. This review summarizes recent advances in the understanding of epigenetic mechanisms underlying SICM, with emphasis on their roles in inflammation, mitochondrial dysfunction, immune–cardiac crosstalk, and cardiomyocyte injury. We further discuss the translational relevance of epigenetic remodeling and highlight the emerging therapeutic potential of epigenetically targeted interventions. Collectively, these findings provide important mechanistic insights into SICM and may support the development of biomarker-guided stratification and more precise therapeutic strategies for septic myocardial dysfunction.