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.