Journal of ethnopharmacology · 2026
Suppression of STING by Acacetin attenuates renal fibrosis via balancing mitophagy and protective nucleoid-phagy.
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Gao Yujiu, Mu Linjie, Liu Chen, Zhao Yue, Cai Rui, Zhu Liting, Rao Fu, Bao Hanxiao, Chen Jinfang, Fan Meixia, Zeng Congcong, Yuan Zhengzhong, Wei Tingting, Cheng Jinguo
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Acacetin (5,7-dihydroxy-4'-methoxyflavone) is a primary active flavonoid extracted from traditional medicinal plants such as Agastache rugosa and Saussurea involucrata. Historically, these herbs have been utilized in Traditional Chinese Medicine to clear heat, eliminate dampness, and treat inflammatory and kidney-related ailments. Despite its potent anti-inflammatory properties, the direct molecular targets of Acacetin and its specific mechanisms regarding mitochondrial quality control (MQC) in the progression of renal fibrosis (RF) remain undefined.
AIM OF THE STUDY: This study aimed to evaluate the anti-fibrotic efficacy of Acacetin and elucidate whether it directly targets the cGAS-STING cascade to restore organelle homeostasis by balancing mitophagy and protective nucleoid-phagy.
METHODS: Molecular dynamics (MD) simulations, microscale thermophoresis (MST), and drug affinity responsive target stability (DARTS) assays were utilized to verify the direct binding between Acacetin and STING. In vivo, wild-type (WT) and STING-knockout (STING-/-) mice were subjected to unilateral ureteral obstruction (UUO) and folic acid nephropathy (FAN) models, and administered Acacetin (40 and 80 mg/kg/d). In vitro, human renal tubular epithelial (HK-2) cells were stimulated with TGF-β or cGAMP. Mitochondrial function, ultrastructure, and dynamic autophagic flux were evaluated using Seahorse XF analysis, transmission electron microscopy (TEM), bafilomycin A1 (BafA1) blockade, tandem fluorescence imaging, and immunofluorescence. Protein and gene expressions were measured via Western blotting and RT-qPCR.
RESULTS: Biophysical assays identified Acacetin as a direct STING inhibitor that bound to the STING protein pocket (Kd = 1.57 μM) and effectively antagonized its cGAMP-induced phosphorylation. Consequently, Acacetin dose-dependently alleviated UUO- and FA-induced renal fibrogenesis, suppressed oxidative stress, and restored mitochondrial respiratory capacity. Mechanistically, Acacetin promoted a functional shift in MQC: it suppressed the initiation phase of maladaptive PINK1/Parkin-mediated "exhaustive over-mitophagy" while facilitating TFAM-LC3-associated "nucleoid-phagy" to selectively clear immunogenic leaked mitochondrial DNA (mtDNA). Crucially, the anti-fibrotic, anti-inflammatory, and MQC-restoring benefits of Acacetin were completely abolished in STING-/- mice, establishing STING as its indispensable pharmacological target.
CONCLUSION: Acacetin ameliorates renal fibrogenesis by directly inhibiting STING, thereby regulating the balance between pathological over-mitophagy and protective nucleoid-phagy. These findings validate the traditional use of Acacetin-rich herbs in treating inflammatory conditions and highlight the monomer as a promising mechanism-based therapeutic candidate for the treatment of chronic kidney disease.
AIM OF THE STUDY: This study aimed to evaluate the anti-fibrotic efficacy of Acacetin and elucidate whether it directly targets the cGAS-STING cascade to restore organelle homeostasis by balancing mitophagy and protective nucleoid-phagy.
METHODS: Molecular dynamics (MD) simulations, microscale thermophoresis (MST), and drug affinity responsive target stability (DARTS) assays were utilized to verify the direct binding between Acacetin and STING. In vivo, wild-type (WT) and STING-knockout (STING-/-) mice were subjected to unilateral ureteral obstruction (UUO) and folic acid nephropathy (FAN) models, and administered Acacetin (40 and 80 mg/kg/d). In vitro, human renal tubular epithelial (HK-2) cells were stimulated with TGF-β or cGAMP. Mitochondrial function, ultrastructure, and dynamic autophagic flux were evaluated using Seahorse XF analysis, transmission electron microscopy (TEM), bafilomycin A1 (BafA1) blockade, tandem fluorescence imaging, and immunofluorescence. Protein and gene expressions were measured via Western blotting and RT-qPCR.
RESULTS: Biophysical assays identified Acacetin as a direct STING inhibitor that bound to the STING protein pocket (Kd = 1.57 μM) and effectively antagonized its cGAMP-induced phosphorylation. Consequently, Acacetin dose-dependently alleviated UUO- and FA-induced renal fibrogenesis, suppressed oxidative stress, and restored mitochondrial respiratory capacity. Mechanistically, Acacetin promoted a functional shift in MQC: it suppressed the initiation phase of maladaptive PINK1/Parkin-mediated "exhaustive over-mitophagy" while facilitating TFAM-LC3-associated "nucleoid-phagy" to selectively clear immunogenic leaked mitochondrial DNA (mtDNA). Crucially, the anti-fibrotic, anti-inflammatory, and MQC-restoring benefits of Acacetin were completely abolished in STING-/- mice, establishing STING as its indispensable pharmacological target.
CONCLUSION: Acacetin ameliorates renal fibrogenesis by directly inhibiting STING, thereby regulating the balance between pathological over-mitophagy and protective nucleoid-phagy. These findings validate the traditional use of Acacetin-rich herbs in treating inflammatory conditions and highlight the monomer as a promising mechanism-based therapeutic candidate for the treatment of chronic kidney disease.