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Войти в исследования Drug design, development and therapy · 2026
GLUT5-Mediated Disruption of the Gut-Testis Axis Deteriorates Olanzapine-Induced Testicular Fibrosis and is Ameliorated by Dapagliflozin.
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Chen Xiao, Zhang Yue, Wang Jie, Ababaikeri Rezeyeguli, Wu Yi-Qing, Liu Zi-Tong, Chen Liang, Huang Yi-Yang, He Su-Mei, Wang Dong-Dong
Аннотация
OBJECTIVE: Olanzapine (OLA)-induced male reproductive toxicity has attracted increasing attention; however, the underlying mechanism of OLA-induced testicular injury remains unclear. The present study aimed to uncover the particular mechanisms involved and to explore potential preventive and therapeutic strategies against OLA-induced testicular injury.
METHODS: This study explored the specific mechanism and potential prevention and treatment methods of OLA-induced testicular injury through transcriptomics, molecular biology, and pathological staining methods.
RESULTS: Transcriptomics analysis and molecular pharmacology approaches revealed that glucose transporter type 5 (GLUT5) mediated the disruption of intestinal tight-junction proteins via activation of the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway (P<0.05 or P<0.01). This process promoted the impairment of the gut-testis axis and upregulated CD28, thereby activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway and facilitating OLA-induced testicular fibrosis (P<0.05 or P<0.01). In addition, dapagliflozin (DAP) could alleviate these pathological changes via downregulating GLUT5, thereby improving OLA-induced testicular fibrosis (P<0.05 or P<0.01).
CONCLUSION: The current study demonstrated for the first time that OLA could induce testicular fibrosis through the activation of the GLUT5/AMPK/mTOR pathway, leading to gut-testis axis dysfunction and activation of the CD28/PI3K/AKT/mTOR pathway. However, DAP could reverse these adverse effects via downregulating GLUT5, thus supporting its potential as a therapeutic agent for OLA-induced testicular fibrosis. The above results could provide novel mechanistic insights and identify new molecular targets for the prevention and treatment of OLA-induced male reproductive toxicity.
METHODS: This study explored the specific mechanism and potential prevention and treatment methods of OLA-induced testicular injury through transcriptomics, molecular biology, and pathological staining methods.
RESULTS: Transcriptomics analysis and molecular pharmacology approaches revealed that glucose transporter type 5 (GLUT5) mediated the disruption of intestinal tight-junction proteins via activation of the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway (P<0.05 or P<0.01). This process promoted the impairment of the gut-testis axis and upregulated CD28, thereby activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway and facilitating OLA-induced testicular fibrosis (P<0.05 or P<0.01). In addition, dapagliflozin (DAP) could alleviate these pathological changes via downregulating GLUT5, thereby improving OLA-induced testicular fibrosis (P<0.05 or P<0.01).
CONCLUSION: The current study demonstrated for the first time that OLA could induce testicular fibrosis through the activation of the GLUT5/AMPK/mTOR pathway, leading to gut-testis axis dysfunction and activation of the CD28/PI3K/AKT/mTOR pathway. However, DAP could reverse these adverse effects via downregulating GLUT5, thus supporting its potential as a therapeutic agent for OLA-induced testicular fibrosis. The above results could provide novel mechanistic insights and identify new molecular targets for the prevention and treatment of OLA-induced male reproductive toxicity.