Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Regulating the BACH1/NCOA4 axis to disrupt UPEC-induced intracellular bacterial communities: Tailin patent formula alleviates bladder epithelial injury by inhibiting ferritinophagy and ferroptosis.
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Wang Qiuhan, Wu Zicong, Zhang Yifan, Song Zhiyong, Deng Xingyu, Gong Xuezhong
Аннотация
BACKGROUND: Intracellular bacterial communities (IBCs), formed following the vesicular escape of uropathogenic Escherichia coli (UPEC), induce injury to bladder epithelial cells (BECs) and contribute to the occurrence of acute urinary tract infection (UTI). Tailin Patent Formula (TLPF) is a patented traditional Chinese medicine formulation used for the treatment of urinary tract infection (UTI) and has been shown to effectively treat UTI and inhibit UPEC vesicular escape. However, the molecular mechanism by which TLPF targets IBCs to alleviate BEC injury remains unclear.
PURPOSE: This study aimed to determine whether TLPF alleviates IBCs-associated BEC injury and to investigate the potential involvement of ferritinophagy- and ferroptosis-related processes associated with the BACH1/NCOA4 axis.
METHODS: IBCs in exfoliated BECs from UTI patient urine samples were detected using Wright-Giemsa staining and immunofluorescence. UTI mouse and in vitro infection models were established using the UPEC CFT073 strain. Inflammation response, IBCs, bacterial burden, and cell viability were evaluated by ELISA, immunofluorescence, CCK-8 and plate count assays. Bioinformatic, RNA sequencing analysis, and molecular docking were performed to identify key targets of TLPF. Oxidative stress and iron homeostasis were evaluated using malondialdehyde (MDA), ferrous ion assays, and ROS detection. Key proteins involved in ferroptosis and ferritinophagy were analyzed by Western blotting, immunofluorescence, immunohistochemistry. Mechanistic studies were conducted using dual-luciferase reporter assays, gene silencing, and pharmacological inhibition.
RESULTS: Clinical analysis revealed a 35% (21/60) IBCs-positive rate in patients with UTI, and TLPF significantly reduced IBCs in exfoliated BECs. In UPEC (CFT073)-infected mice, TLPF inhibited IBCs, reduced bacterial burdens, decreased IL-6 and IL-1β, and alleviated bladder injury. Bioinformatic and RNA sequencing analyses indicated involvement of antioxidant defense and ferroptosis-related pathways, with BACH1 identified as a candidate regulatory target. TLPF attenuated oxidative stress, intracellular iron accumulation, and lipid peroxidation, accompanied by altered expressions of markers related to ferritinophagy and ferroptosis pathways in vitro and in vivo. Dual-luciferase reporter assays suggested that BACH1 might influence NCOA4 promoter activity. Pharmacological inhibition of ferroptosis or autophagy, gene silencing of NCOA4/BACH1, and in vivo BACH1 inhibition also recapitulated the protective effects of TLPF.
CONCLUSION: TLPF may protect BECs against IBCs-induced injury by regulating ferritinophagy and ferroptosis via the BACH1/NCOA4 axis. These findings suggest that TLPF represents a promising therapeutic agent for UTI.
PURPOSE: This study aimed to determine whether TLPF alleviates IBCs-associated BEC injury and to investigate the potential involvement of ferritinophagy- and ferroptosis-related processes associated with the BACH1/NCOA4 axis.
METHODS: IBCs in exfoliated BECs from UTI patient urine samples were detected using Wright-Giemsa staining and immunofluorescence. UTI mouse and in vitro infection models were established using the UPEC CFT073 strain. Inflammation response, IBCs, bacterial burden, and cell viability were evaluated by ELISA, immunofluorescence, CCK-8 and plate count assays. Bioinformatic, RNA sequencing analysis, and molecular docking were performed to identify key targets of TLPF. Oxidative stress and iron homeostasis were evaluated using malondialdehyde (MDA), ferrous ion assays, and ROS detection. Key proteins involved in ferroptosis and ferritinophagy were analyzed by Western blotting, immunofluorescence, immunohistochemistry. Mechanistic studies were conducted using dual-luciferase reporter assays, gene silencing, and pharmacological inhibition.
RESULTS: Clinical analysis revealed a 35% (21/60) IBCs-positive rate in patients with UTI, and TLPF significantly reduced IBCs in exfoliated BECs. In UPEC (CFT073)-infected mice, TLPF inhibited IBCs, reduced bacterial burdens, decreased IL-6 and IL-1β, and alleviated bladder injury. Bioinformatic and RNA sequencing analyses indicated involvement of antioxidant defense and ferroptosis-related pathways, with BACH1 identified as a candidate regulatory target. TLPF attenuated oxidative stress, intracellular iron accumulation, and lipid peroxidation, accompanied by altered expressions of markers related to ferritinophagy and ferroptosis pathways in vitro and in vivo. Dual-luciferase reporter assays suggested that BACH1 might influence NCOA4 promoter activity. Pharmacological inhibition of ferroptosis or autophagy, gene silencing of NCOA4/BACH1, and in vivo BACH1 inhibition also recapitulated the protective effects of TLPF.
CONCLUSION: TLPF may protect BECs against IBCs-induced injury by regulating ferritinophagy and ferroptosis via the BACH1/NCOA4 axis. These findings suggest that TLPF represents a promising therapeutic agent for UTI.