Sepsis-associated acute kidney injury (S-AKI) is a severe complication characterized by high morbidity and mortality, driven by multi-organ dysfunction. Recent evidence suggests that pyroptosis, a form of programmed cell death distinct from apoptosis and necrosis, plays a critical role in the pathophysiology of S-AKI. This review examines the mechanisms of pyroptosis, focusing on inflammasome activation (e.g., NLRP3), caspase-mediated processes, and the role of Gasdermin D in renal tubular damage. We also discuss the contributions of inflammatory mediators, oxidative stress, and potential therapeutic strategies targeting pyroptosis, including inflammasome inhibitors, caspase inhibitors, and anti-inflammatory therapies. Lastly, we highlight the clinical implications and challenges in translating these findings into effective treatments, underscoring the need for personalized medicine approaches in managing S-AKI.

Background: Sepsis and septic shock represent severe infectious conditions with challenging treatments. Preliminary animal studies indicate that Yiqi Huoxue Jiedu Formula (YHJF) may enhance sepsis outcomes, but no clinical trials have been conducted. This research aims to substantiate the efficacy of YHJF in treating sepsis and septic shock.Materials and methods: Mass spectrometry was used to identify the absorbed constituents of YHJF. A retrospective cohort study included sepsis patients from four sub-centers (Feb 24, 2016 - Oct 31, 2024), divided into Western treatment and YHJF plus Western care groups. Propensity score matching ensured baseline comparability. The primary outcome was 28-day mortality, with secondary outcomes including intensive care units (ICU) and hospital stay duration, mechanical ventilation and renal replacement therapy duration, fever duration, and changes in SOFA and APACHE II scores, blood procalcitonin, white blood cell count, and lactate levels after 5 days of treatment. Sepsis shock was analyzed as a subgroup.Results: YHJF absorption mainly includes Shikimates and Phenylpropanoids (33%), Terpenoids (21%), Alkaloids (14%), and Polyketides (11%). A total of 389 sepsis patients were enrolled, with 82 patients being identified as septic shock in the clinical study. The clinical results indicated that YHJF may shorten hospital stay duration, reduce ventilator duration, and improve SOFA score in sepsis. For septic shock, YHJF administration could reduce the duration of non-invasive ventilator use. Notably, YHJF has no effect on improving 28-day mortality for sepsis and septic shock.Conclusion: YHJF can reduce the SOFA score, ventilator use duration, and hospital stay length in sepsis cases and improve non-invasive ventilator use time in septic shock patients, which might attribute to the absorbed components after YHJF administration. Further high-quality trials are needed for confirmation.

The gut is increasingly recognized as a central immunological organ that orchestrates host immune responses and modulates distant mucosal sites, particularly the respiratory tract. In critical illness, disruption of intestinal barrier integrity and microbial homeostasis facilitates the translocation of bacteria, endotoxins, and metabolites into the systemic circulation, thereby contributing to the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The “gut–lung axis” has emerged as a key mechanistic framework linking intestinal dysfunction with pulmonary inflammation and immune dysregulation. Both direct and indirect effects of the gut microbiota play pivotal roles in shaping host immunity. Microbial metabolites, including short-chain fatty acids, bile acids, and tryptophan derivatives, regulate immune cell differentiation and function, particularly influencing the balance between regulatory T cells (Tregs) and T helper 17 (Th17) cells, which are critically involved in lung inflammatory responses. In addition, immune cells originating from the gut and bone marrow contribute to pulmonary immune activity, highlighting the systemic nature of gut-derived immune modulation. Conversely, alterations in lung microbiota can impact intestinal homeostasis, supporting the concept of bidirectional communication within the gut–lung axis. In this review, we comprehensively examine the pathophysiological mechanisms underlying ALI/ARDS across diverse etiological contexts from the perspective of gut–lung interactions, with a focus on immune cell dynamics and microbiota-derived metabolites. We further discuss emerging therapeutic strategies targeting the gut–lung axis, including microbiota modulation, fecal microbiota transplantation, and metabolic interventions. Elucidating these interconnected pathways may provide novel insights into the prevention and treatment of ALI/ARDS and advance the development of integrated organ support strategies in critical care medicine.

Background: Yiqi Huoxue Jiedu Formula (YHJF) is a traditional Chinese medicine formula that has been used as an adjunctive therapy for sepsis for nearly two decades. Previous clinical studies showed that YHJF improves Sequential Organ Failure Assessment (SOFA) scores and modulates gut microbiota in elderly patients with pneumonia-associated sepsis. However, the mechanism by which YHJF protects against sepsis-associated acute lung injury (SALI) remains unclear. Methods: A murine SALI model was established by cecal ligation and puncture (CLP). Therapeutic effects were evaluated by histopathology, micro-CT, pulmonary function assessment, and ELISA. Mechanistic studies included proteomic analysis of lung tissues and LPS-stimulated MH-S macrophages, pharmacological modulation with Mdivi-1 and urolithin A (UA), macrophage-epithelial co-culture, HPLC fingerprinting, UPLC-HRMS, and molecular docking. Results: YHJF significantly improved 7-day survival and ameliorated lung injury, pulmonary edema, respiratory dysfunction, and systemic inflammation in mice with CLP-induced SALI. Proteomic profiling and subsequent functional assays suggested that enhanced mitophagy in macrophages represents a central protective mechanism. In vivo, YHJF increased autophagosome formation and PINK1/Parkin co-localization in BALF-derived alveolar macrophages. In vitro, YHJF restored mitochondrial homeostasis by activating PINK1/Parkin-dependent mitophagy in macrophages. This was accompanied by reduced cytoplasmic mtDNA leakage, downregulated cGAS expression, and suppression of the STING–TBK1–IRF3 pathway and subsequent type I interferon responses. Pharmacological inhibition of mitophagy with Mdivi-1 abolished these protective effects of YHJF, whereas activation with UA augmented them, demonstrating that mitophagy is necessary for YHJF-mediated protection. In a macrophage–epithelial co-culture system, YHJF-treated macrophages alleviated LPS-induced apoptosis in MLE-12 alveolar epithelial cells. Furthermore, chemical analysis integrated with molecular docking identified aloe-emodin, rhein, and genistein as candidate bioactive constituents of YHJF that likely contribute to its regulation of macrophage mitophagy. Conclusion: YHJF protects against SALI by restoring macrophage mitophagy and suppressing mtDNA-STING-mediated inflammatory signalling. These findings support YHJF as a potential therapeutic strategy for sepsis-associated lung injury.

Sepsis‑induced acute lung injury (S‑ALI) is a leading cause of respiratory failure and mortality in intensive care units, characterized by profound biological and clinical heterogeneity that explains the repeated failure of uniform anti‑inflammatory therapies. This variability underscores the urgent need for mechanism‑based patient stratification and precision medicine approaches. Pyroptosis, a regulated inflammatory cell death program driven by gasdermin‑mediated membrane pore formation, has emerged as a critical driver of alveolar‑capillary barrier disruption and cytokine amplification in S‑ALI. The activation of canonical and non‑canonical inflammasome pathways, together with molecular crosstalk within the integrated PANoptosome network, promotes context‑dependent pyroptotic responses across pulmonary endothelial, epithelial and immune cells. Notably, recent insights into lineage plasticity and transcriptional heterogeneity further elucidate the dynamic cellular orchestration of these pathways. Pyroptotic effectors, such as circulating gasdermin D fragments and mature IL‑1β/IL‑18, are detectable in patients with sepsis and acute respiratory distress syndrome, being associated with hyperinflammatory endotypes, disease severity and clinical trajectories. By integrating preclinical mechanistic insights with emerging human biomarker and trial data, the present review positions pyroptosis as a clinically actionable, stratification‑relevant target. The present review highlights current advances in pathway‑specific inhibitors and discusses their potential to enable biomarker‑guided, personalized interventions in critically ill patients.

Background: Sepsis-induced Acute Respiratory Distress Syndrome (ARDS) represents a catastrophic breakdown of systemic homeostasis, where uncontrolled pulmonary inflammation is inextricably linked to gastrointestinal (GI) dysfunction via the “gut-lung axis.” Current management lacks interventions capable of simultaneously modulating systemic inflammation and restoring GI function. Electroacupuncture (EA) at Zusanli (ST36) has emerged as a novel neuromodulatory strategy based on recent neuroanatomical discoveries. This exploratory trial aims to assess the safety and preliminary efficacy of adjunctive EA in mitigating inflammation and improving GI function in patients with sepsis-induced ARDS. Methods: This is a prospective, randomized, controlled trial to be conducted at The Affiliated Traditional Chinese Medicine Hospital,Guangzhou Medical University. One hundred participants diagnosed with sepsis-induced ARDS (2024 Global Definition) will be recruited and randomly assigned (1:1) to either the EA group or the Control group. Both groups will receive standard conventional therapy. The EA group will receive additional bilateral EA stimulation at ST36 (dense-disperse wave, 20/100 Hz) for 30 min daily over 7 consecutive days. The primary outcome is the relative change in serum interleukin-6 (IL-6) levels from baseline (Day 0) to the end of treatment (Day 8). Additional inflammatory biomarkers, including white blood cell count, neutrophil percentage, procalcitonin (PCT), C-reactive protein (CRP), and serum amyloid A (SAA), will be evaluated as secondary exploratory outcomes. Secondary outcomes include objective GI functional parameters (Gastric Residual Volume, bowel sounds, defecation frequency, and Bristol Stool Scale score) and safety profiles. As an exploratory trial, the sample size is designed to estimate the effect size and its precision to inform the design of a future definitive trial. Results: The trial is currently in the patient recruitment phase. We anticipate that this study will evaluate predefined feasibility parameters, including recruitment, consent, treatment completion, and outcome data completeness, alongside preliminary biological signals regarding the modulation of the gut-lung axis. Discussion: This pilot trial is grounded in the neuroanatomical basis of the “gut-lung axis.” We hypothesize that EA at ST36 will activate the vagal-adrenal anti-inflammatory reflex, thereby disrupting the pathogenic cycle in critical illness. By simultaneously targeting both the immune and gastrointestinal systems, this study seeks to explore the specific biological signal and preliminary efficacy of EA, providing estimates of treatment effect to inform the design of a future definitive trial. The findings will not only provide estimates of the predefined feasibility parameters and preliminary efficacy signals but also lay the essential groundwork for designing larger, multicenter investigations into acupuncture's role in critical care. Clinical Trial Registration: https://itmctr.ccebtcm.org.cn/mgt/project/view/2101619906628943872 , identifier ITMCTR2026001814.