Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Physcion attenuates renal fibrosis by disrupting PKM2-FAK1 interaction and suppressing the FAK1/ERK signaling axis.
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Zhang Zhirui, Wang Lin, Zou Songsong, Lei Ming, Tong Kaixiang, Zhang Meijuan, Xu Wuqin, Cheng Long, Yang Chunyan, Chen Lili, Cao Jing, Jiao Hao
Аннотация
BACKGROUND: Renal fibrosis (RF) is the final common pathway of chronic kidney disease with limited therapeutic options. Pyruvate kinase M2 (PKM2) is upregulated in fibrotic kidneys and promotes pro-fibrotic signaling. Physcion (PHY), a natural anthraquinone, exerts organ-protective effects, but its direct targets and systemic mechanisms in RF remain unclear.
PURPOSE: This study aims to elucidate the molecular mechanism by which PHY alleviates RF, and to identify its direct targets and downstream signaling pathways.
METHODS: TGF-β1-induced HK-2 cells and unilateral ureteral obstruction (UUO) mice were used. The PKM2-FAK1 interaction was identified by Lip-MS, IP-MS, Co-IP, and molecular docking. The PHY binding site on PKM2 was determined via site-directed mutagenesis, and AAV-mediated knockdown was used to confirm PKM2 dependency in vivo. Multi-omics with canonical correlation analysis (CCA) and clinical RF specimens were also analyzed.
RESULTS: PHY alleviated RF in UUO mice with reduced fibrotic lesions and improved renal function. Mechanistically, PHY directly binds PKM2 at the F26 residue, and disrupts the PKM2-FAK1 physical interaction. Consequently, PHY inhibited FAK1/ERK1/2 phosphorylation and reduced pro-fibrotic markers, effects abrogated by PKM2/FAK1 knockdown and the F26A mutation. AAV-mediated PKM2 knockdown eliminated PHY's renoprotective effect. Additionally, PHY remodeled gut microbiota and altered metabolic profiles in UUO mice. Clinically, serum PKM2 activity was elevated in CKD patients and correlated with renal dysfunction markers.
CONCLUSION: This research identifies that PHY targets the PKM2-F26 residue, disrupts PKM2-FAK1 interaction, thereby inhibiting the FAK1/ERK pathway. Meanwhile, PHY synergistically modulates the gut-kidney metabolic axis, providing a promising therapeutic candidate and new target for RF.
PURPOSE: This study aims to elucidate the molecular mechanism by which PHY alleviates RF, and to identify its direct targets and downstream signaling pathways.
METHODS: TGF-β1-induced HK-2 cells and unilateral ureteral obstruction (UUO) mice were used. The PKM2-FAK1 interaction was identified by Lip-MS, IP-MS, Co-IP, and molecular docking. The PHY binding site on PKM2 was determined via site-directed mutagenesis, and AAV-mediated knockdown was used to confirm PKM2 dependency in vivo. Multi-omics with canonical correlation analysis (CCA) and clinical RF specimens were also analyzed.
RESULTS: PHY alleviated RF in UUO mice with reduced fibrotic lesions and improved renal function. Mechanistically, PHY directly binds PKM2 at the F26 residue, and disrupts the PKM2-FAK1 physical interaction. Consequently, PHY inhibited FAK1/ERK1/2 phosphorylation and reduced pro-fibrotic markers, effects abrogated by PKM2/FAK1 knockdown and the F26A mutation. AAV-mediated PKM2 knockdown eliminated PHY's renoprotective effect. Additionally, PHY remodeled gut microbiota and altered metabolic profiles in UUO mice. Clinically, serum PKM2 activity was elevated in CKD patients and correlated with renal dysfunction markers.
CONCLUSION: This research identifies that PHY targets the PKM2-F26 residue, disrupts PKM2-FAK1 interaction, thereby inhibiting the FAK1/ERK pathway. Meanwhile, PHY synergistically modulates the gut-kidney metabolic axis, providing a promising therapeutic candidate and new target for RF.