Neddylation-dependent CUL3-KLHL12 E3 ligase drives microglial oxidative stress and neuroinflammation in traumatic brain injury by targeting GCLM for degradation.

Multi-omics integration reveals TIM-4 as a master regulatory hub of neuroinflammation and neuronal cell death

TIM-4 is established as a critical driver of neuroinflammation-associated neuronal death in TBI, representing a promising therapeutic target for TBI-related cognitive dysfunction.

Isorhoifolin regulates S1PR3-CK2-GSK3β axis and promotes neurite regrowth and functional recovery after traumatic brain injury.

BACKGROUND Traumatic brain injury (TBI) disrupts anatomical structure and cellular signaling, yet the molecular mechanisms governing endogenous repair remain incompletely defined. Accumulating evidence implicate an increased risk of developing to neurodegenerative diseases for TBI patients, in part through chronic neuroinflammation, protein aggregation, and progressive synaptic dysfunction. However, a critical unmet need is that no approved medicine directly promotes neurite regrowth and functional recovery after TBI. PURPOSE To identify candidate compounds that can promote neurite regrowth of injured brain neurons and improve functional outcome of TBI mice. The mechanism of action of the lead compound will be determined. STUDY DESIGN Through an extensive screening of plant extracts, we have identified a nature compound, isorhoifolin, that promotes neurite regrowth of injured cortical and hippocampal neurons. Functional assays were conducted to assess behavioral efficacy and the direct protein targets of isorhoifolin were identified. RESULTS Using complementary in vitro, ex vivo, and in vivo models of TBI, we demonstrated that isorhoifolin attenuated both cytosolic and mitochondrial reactive oxygen species, highlighting its role in redox homeostasis. Comparative structure-activity analyses revealed that the closely related flavonoids exhibited divergent biological efficacy, indicating that specific chemical features determine functional outcomes. In vivo, isorhoifolin crossed the blood-brain barrier and significantly improved motor coordination following experimental TBI. Transcriptomic profiling and cellular thermal shift assay (CETSA) further revealed that isorhoifolin bound directly to sphingosine-1-phosphate receptor-3 (S1PR3) and exerted temporally structured effects on injury-responsive networks. In human transcriptomic data, we found activation of S1P receptor-related pathways in TBI patients and the expression of S1PR3 was increased approximately 40%. Importantly, the current work delineates a neuron-centric role for S1PR3 in regulating structural repair that is mechanistically distinct from the known functions of S1PRs in immune cells. Biochemical assays supported a model in which isorhoifolin facilitates neurite repair through inhibiting neuronal S1PR3-CK2-GSK3β signaling axis. In parallel, isorhoifolin interacted directly with N-ribosyldihydronicotinamide:quinone reductase 2 (NQO2) based on proteomic CESTA, and genetic knockdown as well as inhibition of NQO2 in astrocytes promote neurite regrowth of injured cortical neurons. CONCLUSION Together, these findings define mechanistically distinct yet coordinated neuronal and astrocytic pathways that are responsible for isorhoifolin-enhanced structural and functional recovery after TBI, and identify S1PR3 and NQO2 as direct and druggable targets.

3-Hydroxydehydroleucodin ameliorates neuroinflammation and ischemic brain injury by blocking the TRIM21-PRDX1 interaction.

Dual Regulation of ACSL3 by TRIM33-Mediated Ubiquitination and NBR1-Dependent Autophagy: A Therapeutic Target for Cerebral Ischemia-Reperfusion Injury.

BACKGROUND Cerebral ischemia-reperfusion injury (CIRI) is a key contributor to stroke-related neurological damage, but the functional interplay between autophagy and ferroptosis-two critical pathological processes-remains poorly understood. METHODS Using oxygen-glucose deprivation/reperfusion in PC12 cells and middle cerebral artery occlusion (MCAO) in rats, we combined molecular, pharmacological, and imaging approaches to investigate how autophagy regulates the ferroptosis suppressor acyl-CoA synthetase long-chain family member 3 (ACSL3). RESULTS Ischemia-reperfusion triggered hyperactivated autophagy, which promoted ferroptosis by selectively targeting ACSL3 for degradation via the autophagy receptor neighbor of BRCA1 gene 1 protein (NBR1). We further identified that tripartite motif-containing protein 33 (TRIM33), an E3 ubiquitin ligase induced after ischemia, directly ubiquitinates ACSL3 and facilitates its proteasomal degradation. This ubiquitin-mediated pathway acted synergistically with autophagy to control ACSL3 stability. Pharmacological inhibition of autophagy with curcumin derivative 5g (CUR5g) restored ACSL3 protein levels and suppressed ferroptosis. In MCAO rats, CUR5g-administered alone or in combination with the ferroptosis inhibitor Ferfluor-1-significantly improved functional recovery and reduced brain injury. CONCLUSION Our study reveals a novel autophagy-NBR1/TRIM33-ACSL3 regulatory axis that drives ferroptosis in CIRI, highlighting a promising therapeutic strategy for ischemic stroke through cotargeting autophagy and ferroptosis. Antioxid. Redox Signal. 00, 000-000.

Microglial Deubiquitinase OTUD7B Stabilizes STAT3 to Promote Neuroinflammation and Cognitive Decline in Alzheimer's Disease

Findings uncover an OTUD7B‐STAT3 signaling axis that sustains microglial‐driven neuroinflammation and identify OTUD7B as a potential therapeutic target for mitigating neurodegenerative pathology in AD.

Pyrroloquinoline Quinone Attenuates Traumatic Brain Injury‐Induced Secondary Damage by Activating PINK1/Parkin‐Mediated Mitophagy and Suppressing ASS1/CPS1‐Driven Arginine Biosynthesis

ABSTRACT Aims Pyrroloquinoline quinone (PQQ) was reported to be neuroprotective after experimental traumatic brain injury (TBI), but its mechanisms remain undefined. We tested whether PQQ protects against TBI in mice and identified the associated pathways. Methods Male C57BL/6 mice received intraperitoneal PQQ (6.25, 12.5 or 25 mg/kg) immediately after controlled cortical impact. Mortality, modified neurological severity score (mNSS) and beam balance were followed to day 14; histopathology, immunofluorescence, western blot, ELISA and ATP assays were performed on day 3. Transcriptomics, metabolomics, network pharmacology and docking were integrated to identify candidate mechanisms. Results PQQ reduced mortality (lowest at 12.5 mg/kg) and dose‐dependently improved neurological deficits, neuronal apoptosis, brain edema, pro‐inflammatory cytokines, and oxidative stress; the mNSS and beam balance benefits persisted to day 14. At 12.5 mg/kg, multi‐omics and network pharmacology identified arginine biosynthesis, mediated by argininosuccinate synthetase 1 (ASS1) and carbamoyl phosphate synthetase 1 (CPS1), as the top‐ranked pathway suppressed by PQQ; docking predicted binding of PQQ to both enzymes, suggesting putative targets pending validation. PQQ concurrently restored PTEN‐induced kinase 1 (PINK1)/Parkin‐mediated mitophagy and ATP production. Conclusion PQQ attenuates secondary injury after TBI in male mice, in association with increased markers of PINK1/Parkin‐mediated mitophagy initiation and suppressed ASS1/CPS1‐driven arginine biosynthesis, identifying a candidate dual‐axis mechanism and nominating the mitophagy‐arginine axis as a target for neuroprotection in TBI.