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The STING pathway and its induction of autophagy initiate a potent immune defense response upon the recognition of pathogenic DNA. However, this protective response is minimal, as STING activation worsens organ damage, and abnormal autophagy is observed during progressive sepsis. Whether and how the STING pathway affects autophagic flux during sepsis-induced acute lung injury (sALI) are currently unknown. Here, we demonstrate that the level of circulating mtDNA and degree of STING activation are increased in sALI patients. Furthermore, STING activation was found to play a pivotal role in mtDNA-mediated lung injury by evoking an inflammatory storm and disturbing autophagy. Mechanistically, STING activation interferes with lysosomal acidification in an interferon (IFN)-dependent manner without affecting autophagosome biogenesis or fusion, aggravating sepsis. Induction of autophagy or STING deficiency alleviated lung injury. These findings provide new insights into the role of STING in the regulatory mechanisms behind extrapulmonary sALI.

Intestinal ischemia reperfusion (I/R) injury is the important pathogenesis for acute intestinal barrier disruption. The STING signaling is associated with gut homeostasis and barrier integrity. However, the biological function and regulation of STING signaling in intestinal I/R injury are not yet fully understood. As the ligand of STING signaling, the mitochondrial DNA (mtDNA) has been found to be associated with necroptosis. It still remains unknown whether mtDNA-STING signaling triggers intestinal necroptosis in intestinal I/R injury. We found that circulating RIPK3 was significantly increased and had a positive correlation with markers of enterocyte injury in critically ill patients with intestinal injury. Moreover, the levels of circulating mtDNA were also associated with the levels of circulating RIPK3. To explore the relationship between mtDNA and intestinal necroptosis, mice were treated with the intraperitoneal injection of mtDNA, and necroptosis signaling was remarkably activated and the inhibition of necroptosis alleviated mtDNA-induced intestinal injury. Furthermore, STING knockout mice showed an alleviated intestinal necroptosis. In intestinal I/R injury, mtDNA was released from IECs and necroptosis was also triggered, companied with a significant decrease of RIPK3 in the intestine. STING knockout mice markedly attenuated intestinal necroptosis and intestinal I/R injury. Finally, we found that mtDNA-mediated STING signaling triggered necroptosis through synergistic IFN and TNF-α signaling in primary IECs. Our results indicated that mtDNA-STING signaling can contribute to intestinal I/R injury by promoting IEC necroptosis. STING-mediated both IFN and TNF-α signaling can trigger intestinal nercroptosis.

The discovery of STING-related innate immunity has recently provided a deep mechanistic understanding of immunopathy. While the detrimental effects of STING during sepsis had been well documented, the exact mechanism by which STING causes lethal sepsis remains obscure. Through single-cell RNA sequence, genetic approaches, and mass spectrometry, we demonstrate that STING promotes sepsis-induced multiple organ injury by inducing macrophage ferroptosis in a cGAS- and interferon-independent manner. Mechanistically, Q237, E316, and S322 in the CBD domain of STING are critical binding sites for the interaction with the coiled-coil domain of NCOA4. Their interaction not only triggers ferritinophagy-mediated ferroptosis, but also maintains the stability of STING dimers leading to enhanced inflammatory response, and reduces the nuclear localization of NCOA4, which impairs the transcription factor coregulator function of NCOA4. Meanwhile, we identified HET0016 by high throughput screening, a selective 20-HETE synthase inhibitor, decreased STING-induced ferroptosis in peripheral blood mononuclear cells from patients with sepsis and mortality in septic mice model. Our findings uncover a novel mechanism by which the interaction between STING and NCOA4 regulates innate immune response and ferroptosis, which can be reversed by HET0016, providing mechanistic and promising targets insights into sepsis.

Backgrounds The stimulator of interferon genes (STING) is an important driver in various inflammatory diseases. Methods and results Here, we have demonstrated that inhibition of RIPK3 and MLKL dampens STING signaling, indicating that necroptosis may be involved in sustaining STING signaling. Furthermore, RIPK3 knockout in HT‐29 cells significantly suppressed STING signaling. Mechanistically, RIPK3 inhibits autophagic flux during STING activation. RIPK3 knockout inhibits STING signaling by intensifying STING autophagy. In contrast, MLKL regulates the STING pathway bidirectionally. MLKL deficiency enhances STING signaling, whereas suppression of MLKL‐mediated pore formation restricts STING signaling. Mechanistically, upon abrogating the pro‐necroptotic activity of MLKL, MLKL bound to activated STING is secreted to the extracellular space, where it restricts TBK1 and IRF3 recruitment. Targeting necroptotic signaling ameliorates STING activation during DMXAA‐induced intestinal injury and sepsis. Conclusions These findings elucidate molecular mechanisms linking necroptosis to the STING pathway, and suggest a potential benefit of therapeutic targeting of necroptosis in STING‐driven inflammatory diseases. 1. Necroptosis is not solely a downstream effect of STING signalling. 2. RIPK3 participates in inhibiting autophagy and sustains STING signalling. 3. Intrinsic MLKL bound to activated STING is secreted to the extracellular space, which is restrained by the pro‐necroptotic activity of MLKL.

Klebsiella pneumoniae (KP) infections represent a significant global health challenge, characterized by severe inflammatory sequelae and escalating antimicrobial resistance. This comprehensive review elucidates the complex interplay between macrophages and KP, encompassing pathogen recognition mechanisms, macrophage activation states, cellular death pathways, and emerging immunotherapeutic strategies. We critically analyze current literature on macrophage pattern recognition receptor engagement with KP-associated molecular patterns. The review examines the spectrum of macrophage responses to KP infection, including classical M1 polarization and the newly described M(Kp) phenotype, alongside metabolic reprogramming events such as glycolytic enhancement and immune responsive gene 1 (IRG1)–itaconate upregulation. We systematically evaluate macrophage fate decisions in response to KP, including autophagy, apoptosis, pyroptosis, and necroptosis. Furthermore, we provide a critical assessment of potential future therapeutic modalities. Given the limitations of current treatment paradigms, elucidating macrophage–KP interactions is imperative. Insights gained from this analysis may inform the development of novel immunomodulatory approaches to augment conventional antimicrobial therapies, potentially transforming the clinical management of KP infections. Graphical Abstract

Guanine nucleotide exchange factors (GEFs) and their small GTPase substrates constitute a fundamental regulatory system that governs diverse cellular processes, including cytoskeletal dynamics, membrane trafficking, and transcriptional regulation. Since their discovery, GEFs have been recognized as molecular switches that activate small GTPases by catalyzing GDP‐to‐GTP exchange, thereby playing pivotal roles in cellular signaling and homeostasis. Despite extensive research, key gaps remain in understanding the spatiotemporal regulation of GEF isoforms, their functional redundancy in disease, and the development of isoform‐specific drugs. This review examines the regulatory mechanisms and physiological roles of GEFs, highlighting their growing potential as therapeutic targets. We explore the phylogenetic classification of GEFs into major families (Ras, Rho, Rab, and ArfGEFs) and their regulatory networks, which encompass subcellular localization, posttranslational modifications, and scaffolding interactions. Special emphasis is placed on GEF–H1, a microtubule‐regulated RhoGEF, and its roles in cytoskeletal remodeling, cancer metastasis, and immune responses. We also examine GEF dysregulation in diseases like cancer, neurodegeneration, and cardiovascular disorders, and assess current therapies, such as small‐molecule inhibitors and emerging PROTAC technology. This review connects GEF biology with clinical applications by combining basic research with translational insights, providing guidance for precision medicine and novel therapeutic strategies targeting GEF‐related diseases. This review comprehensively examines the regulatory mechanisms and physiological roles of guanine nucleotide exchange factors (GEFs) and their small GTPase substrates, highlighting their significance in cellular processes and disease pathogenesis. We discuss the classification, core regulatory mechanisms, and dysregulation of GEFs in cancer, neurodegenerative diseases, and immune disorders. Additionally, we evaluate current therapeutic strategies targeting GEFs, including small‐molecule inhibitors and emerging technologies like PROTACs, providing insights for future drug development.

Hypervirulent Klebsiella pneumoniae (hvKP) is a highly lethal opportunistic pathogen that elicits more severe inflammatory responses compared to classical Klebsiella pneumoniae (cKP). In this study, we investigated the interaction between hvKP infection and the anti-inflammatory immune response gene 1 (IRG1)-itaconate axis. Firstly, we demonstrated the activation of the IRG1-itaconate axis induced by hvKP, with a dependency on SYK signaling rather than STING. Importantly, we discovered that exogenous supplementation of itaconate effectively inhibited excessive inflammation by directly inhibiting SYK kinase at the 593 site through alkylation. Furthermore, our study revealed that itaconate effectively suppressed the classical activation phenotype (M1 phenotype) and macrophage cell death induced by hvKP. In vivo experiments demonstrated that itaconate administration mitigated hvKP-induced disturbances in intestinal immunopathology and homeostasis, including the restoration of intestinal barrier integrity and alleviation of dysbiosis in the gut microbiota, ultimately preventing fatal injury. Overall, our study expands the current understanding of the IRG1-itaconate axis in hvKP infection, providing a promising foundation for the development of innovative therapeutic strategies utilizing itaconate for the treatment of hvKP infections. Graphical abstract

Although extensive research has been conducted on cation vacancies in photocatalysts, the significance of vacancy defects in photocatalytic reactions and deep‐going understanding of the intrinsic mechanisms are still limited. Herein, an appropriate introduction of zinc vacancies on ZnIn2S4 (ZIS) is rationally designed through Er or La (Er/La)‐doping. Aberration‐corrected scanning transmission electron microscopy (STEM) directly demonstrates distinct zinc vacancies (VZn), which is also confirmed by electron spin resonance analysis. The results of experiments and density functional theory (DFT) calculations manifest that Er/La‐doping not only promotes the formation of VZn but also enhances the built‐in electric field, thus facilitating the rapid transfer of carriers. In addition, femtosecond transient absorption spectroscopy (fs‐TAS) reveals that VZn induces a supplementary charge transfer pathway, thereby enhancing charge separation efficiency. As a result, the desired photocatalytic CO2 reduction reaction (CO2RR) to syngas capacity is finally achieved on Er0.2‐ZIS, with tunable H2/CO ratios, exceeding that of untreated ZIS by over 2 times. This study not only exploits a novel avenue to develop high‐activity cation vacancies photocatalysts but also provides new perspectives in regulating the photogenerated carrier dynamics. Atomic‐scale STEM imaging directly confirms the existence of zinc vacancy defects (VZn). DFT calculations demonstrate that electron‐rich Er3+ centers and electron‐deficient VZn sites collectively establish an interfacial electric field. Femtosecond‐transient absorption spectroscopy reveals that VZn can generate trap states in Erx‐ZIS, which effectively capture photogenerated holes.

Gasdermins (GSDMs) serve as pivotal executors of pyroptosis and play crucial roles in host defence, cytokine secretion, innate immunity, and cancer. However, excessive or inappropriate GSDMs activation is invariably accompanied by exaggerated inflammation and results in tissue damage. In contrast, deficient or impaired activation of GSDMs often fails to promptly eliminate pathogens, leading to the increasing severity of infections. The activity of GSDMs requires meticulous regulation. The dynamic modulation of GSDMs involves many aspects, including autoinhibitory structures, proteolytic cleavage, lipid binding and membrane translocation (oligomerization and pre-pore formation), oligomerization (pore formation) and pore removal for membrane repair. As the most comprehensive and efficient regulatory pathway, posttranslational modifications (PTMs) are widely implicated in the regulation of these aspects. In this comprehensive review, we delve into the complex mechanisms through which a variety of proteases cleave GSDMs to enhance or hinder their function. Moreover, we summarize the intricate regulatory mechanisms of PTMs that govern GSDMs-induced pyroptosis.