Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Theaflavin protects against ischemic stroke by inhibiting PLA2G4C-driven lipid remodeling and ferroptosis.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Yang Yang, Tan Quandan, Yao Meiling, Xie Yang, Zhu Guoliang, Chen Xiu, Yang Jie, Luo Ying
Аннотация
BACKGROUND: Ferroptosis contributes to secondary brain injury after ischemic stroke, but upstream phospholipid remodeling mechanisms remain unclear.
PURPOSE: We investigated whether PLA2G4C promotes post-ischemic ferroptosis and whether theaflavin confers neuroprotection by targeting this pathway.
STUDY DESIGN: Combined in vivo and in vitro mechanistic study using rat MCAO/R and OGD/R models.
METHODS: RNA sequencing and siRNA-mediated knockdown assessed PLA2G4C function in MCAO/R rats and OGD/R neurons. Virtual screening identified theaflavin as a candidate modulator; surface plasmon resonance (SPR) compared binding affinities of three shortlisted compounds to recombinant PLA2G4C; cellular thermal shift assay (CETSA) assessed intracellular target engagement; LC-MS/MS lipidomics characterized PE-AA remodeling.
RESULTS: PLA2G4C was significantly upregulated in ischemic brain tissue, predominantly in neurons, and was associated with ferroptosis-related transcriptional signatures. Pla2g4c silencing reduced infarct size and improved neurological outcomes, effects reversed by RSL3. PLA2G4C knockdown reduced PE-AA accumulation, attenuated ACSL4 upregulation, and preserved GPX4. SPR confirmed theaflavin as the strongest binder among three candidates (KD = 243 nM vs. 2.11 μM and 8.69 μM for the comparators). CETSA supported intracellular target engagement. Theaflavin reduced PLA2G4C abundance and PE-AA content, attenuated lipid peroxidation, and improved neuronal survival; PE-AA supplementation or PLA2G4C overexpression diminished these benefits.
CONCLUSION: PLA2G4C drives post-ischemic ferroptosis through PE-AA accumulation. SPR and CETSA support direct binding and intracellular engagement of PLA2G4C by theaflavin, providing mechanistic evidence for its anti-ferroptotic and neuroprotective effects.
PURPOSE: We investigated whether PLA2G4C promotes post-ischemic ferroptosis and whether theaflavin confers neuroprotection by targeting this pathway.
STUDY DESIGN: Combined in vivo and in vitro mechanistic study using rat MCAO/R and OGD/R models.
METHODS: RNA sequencing and siRNA-mediated knockdown assessed PLA2G4C function in MCAO/R rats and OGD/R neurons. Virtual screening identified theaflavin as a candidate modulator; surface plasmon resonance (SPR) compared binding affinities of three shortlisted compounds to recombinant PLA2G4C; cellular thermal shift assay (CETSA) assessed intracellular target engagement; LC-MS/MS lipidomics characterized PE-AA remodeling.
RESULTS: PLA2G4C was significantly upregulated in ischemic brain tissue, predominantly in neurons, and was associated with ferroptosis-related transcriptional signatures. Pla2g4c silencing reduced infarct size and improved neurological outcomes, effects reversed by RSL3. PLA2G4C knockdown reduced PE-AA accumulation, attenuated ACSL4 upregulation, and preserved GPX4. SPR confirmed theaflavin as the strongest binder among three candidates (KD = 243 nM vs. 2.11 μM and 8.69 μM for the comparators). CETSA supported intracellular target engagement. Theaflavin reduced PLA2G4C abundance and PE-AA content, attenuated lipid peroxidation, and improved neuronal survival; PE-AA supplementation or PLA2G4C overexpression diminished these benefits.
CONCLUSION: PLA2G4C drives post-ischemic ferroptosis through PE-AA accumulation. SPR and CETSA support direct binding and intracellular engagement of PLA2G4C by theaflavin, providing mechanistic evidence for its anti-ferroptotic and neuroprotective effects.