Jinglin Li

Background Mitoxyperilysis, a recently discovered mitochondria-dependent lytic cell death pathway, has been implicated in innate immune activation and metabolic stress. Its contribution to sepsis-associated immune dysfunction remains unclear. Methods Multi-cohort transcriptomic and single-cell sequencing datasets were integrated to systematically characterize Mitoxyperilysis in sepsis. Machine learning, immune landscape profiling, pseudotime analysis, and cell–cell communication analyses were employed to identify key regulators and underlying mechanisms. Results Mitoxyperilysis was markedly activated in sepsis and associated with profound immune heterogeneity. Four Mitoxyperilysis-related hub genes were identified, among which TLR8 emerged as the central regulator, showing consistent upregulation and superior diagnostic accuracy across independent cohorts. At the single-cell level, Mitoxyperilysis activity was predominantly localized to monocytes and neutrophils. TLR8 was enriched in early developmental monocytes and was associated with extensive rewiring of inflammatory communication networks, including enhanced monocyte–neutrophil interactions. These findings suggest a potential Mitoxyperilysis–TLR8–monocyte immune remodeling axis in sepsis. Conclusions Our study identifies Mitoxyperilysis as a previously unrecognized feature of sepsis and proposes TLR8-driven monocyte immune remodeling as a potential mechanistic link between mitochondrial lytic cell death and immune dysregulation. This work provides novel insights into sepsis pathogenesis and highlights TLR8 as a candidate biomarker and therapeutic target.

Background: Traumatic brain injury (TBI) poses a significant threat to human health. Ferroptosis has been reported to promote secondary brain damage, but whether ferroptosis affects injury se-verity is currently unknown. Objective: We aim to explore the relationship between ferroptosis in brain and neurological deficits in TBI models. Methods: Male Sprague-Dawley rats were randomly divided into four groups: a sham group, a mild TBI group (mTBI), a mild-moderate TBI group (mmTBI), and a severe TBI group (sTBI). Rat model of TBI was established, neurological function deficits were evaluated using modified Neurological Severity Score (mNSS). Magnetic resonance imaging (MRI), transmission electron microscopy (TEM), and Prussian blue staining were em-ployed to observe ferroptosis in the rat brains. Western blot analysis was used to detect the ex-pression of ferroptosis-related proteins, and the correlation between mNSS scores and the ex-pression of these markers was analyzed. Results: 1) MRI scans showed the TBI groups exhibited high itensity in the T2WI sequence and low intensity in the T2*WI sequence, indicating iron dep-osition. 2) TEM and Prussian blue staining showed neurons in the TBI group exhibited iron-positive cells and morphological changes of ferroptosis. 3) Western blot showed ferropto-sis-related proteins were significantly reduced in the mmTBI and sTBI groups. 4) MDA levels were significantly elevated in TBI groups, and mNSS scores increased with injury severity. Correlation analysis revealed a significant negative correlation between mNSS scores and ferroptosis inhibi-tors expression, and a positive correlation with MDA levels. Conclusion: Iron deposition and ferroptosis occur in brain tissue after TBI, and they are closely associated with the severity of neurological impairment.

Background: Traumatic brain injury (TBI) is a critical condition that significantly endangers hu-man health. Investigating the mechanisms underlying secondary injury in TBI can facilitate early intervention and treatment strategies. The metabolism of intracellular iron is pivotal in the sec-ondary injury process following TBI, with ferroptosis identified as a contributing factor. However, research exploring the relationship between the extent of ferroptosis and the severity of neuro-logical deficits across various TBI models is still limited. Objective: This study seeks to examine the association between ferroptosis in brain tissues and neurological impairments in TBI models with differing injury severities, thereby providing a theoretical framework for understanding the mechanisms and standardizing treatment approaches for TBI. Methods: 36 Male Sprague-Dawley rats were randomly assigned to four groups: a sham group, a mild TBI group (mTBI), a mild-moderate TBI group (mmTBI), and a severe TBI group (sTBI). A rat model of TBI with var-ying injury levels was established using the Feeney free-fall impact method. Neurological function deficits were assessed using the modified Neurological Severity Score (mNSS). Magnetic reso-nance imaging (MRI), transmission electron microscopy (TEM), and Prussian blue staining were utilized to examine iron deposition and ferroptosis in the cortical regions of the rat brains. Western blot analysis was conducted to evaluate the expression of ferroptosis-related molecular markers, and the correlation between mNSS scores and these markers was analyzed. Results: 1) MRI scans indicated that, in comparison to the sham group, the TBI groups displayed elevated signals in the T2WI and T2*WI sequences, signifying brain injury, edema, and hemorrhage. T2*WI revealed diminished signals surrounding the injured areas, indicating iron deposition. 2) TEM analysis revealed that neurons in the TBI group exhibited morphological alterations, including mitochon-drial atrophy, membrane thickening, and partial rupture of the outer membrane. 3) Prussian blue staining demonstrated a progressive increase in iron-positive cells correlating with TBI severity. 4) Western blot results indicated that the expression levels of ferroptosis-related proteins (FTH1 and GPX4) were significantly lower in the mmTBI and sTBI groups compared to the sham group. 5) MDA levels were markedly elevated in the TBI groups, and mNSS scores increased with the se-verity of injury. Correlation analysis revealed a significant negative correlation between mNSS scores and the expression of ferroptosis inhibitors FTH1 and GPX4, alongside a positive correlation with MDA levels. Conclusion: Iron deposition and ferroptosis occur in brain tissue following TBI, and they are closely linked to the severity of neurological impairment.