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Transcriptomic Modulation of Inflammasome-Related Genes Following Metformin Administration in Breast Cancer Patients
Alireza Malayeri1, Mehdi Etemad Nezhad2, Farrokh Ramesh3
1Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Introduction:
Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of paclitaxel therapy. The inflammasome complex, including apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, and NOD-like receptor family pyrin domain-containing 3 (NLRP3), is implicated in inflammatory signaling pathways related to neuropathy. This study aimed to evaluate transcriptomic changes in genes involved in the inflammasome pathway in breast cancer patients, with a specific focus on metformin treatment initiated after the onset of neuropathy.
Materials And Methods:
A total of 51 breast cancer patients receiving paclitaxel were included (26 controls, 25 metformin). Metformin was initiated following the clinical onset of neuropathy. Plasma samples were collected at baseline, cycle 6, and cycle 12. Expression levels of ASC, Caspase-1, and NLRP3 were quantified as fold-change. Statistical analyses included normality testing (Shapiro-Wilk), temporal comparisons (Friedman or repeated-measures ANOVA), group comparisons (Mann-Whitney U-test), correlation (Spearman), and Receiver Operating Characteristic (ROC) analysis.
Results:
No significant baseline differences were observed between groups. In the control group, ASC expression increased over time (p = 0.0005), while Caspase-1 and NLRP3 showed no significant temporal changes. In neuropathic patients, ASC (p < 0.0001), Caspase-1 (p = 0.0007), and NLRP3 (p = 0.04) expression levels were higher in the metformin group. ROC analysis demonstrated moderate discriminatory ability for ASC (AUC = 0.74) and Caspase-1 (AUC = 0.70), whereas NLRP3 showed weaker performance (AUC = 0.62). Correlation analysis revealed positive associations between ASC and Caspase-1, suggesting coordinated gene expression. These findings reflect transcriptomic modulation rather than functional inflammasome activation.
Conclusion:
Metformin administration after neuropathy onset was associated with transcriptomic changes in genes involved in the inflammasome pathway. However, these findings should be interpreted cautiously, as plasma RNA may not reflect protein activity or neural tissue processes, and further validation studies are required.
