Cisplatin Induces Inflammation by Activating IL-6 via Suppressing rno-let-7g-5p and rno-let-7f-5p Expression in...

Cisplatin is a widely used chemotherapeutic agent; however, its therapeutic efficacy is often limited by severe cytotoxic side effects, particularly gastrointestinal toxicity, which manifests as intestinal mucositis. MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in both normal physiological and pathological processes by regulating gene expression. However, their role in cisplatin-induced gastrointestinal toxicity remains unclear. In this study, we investigated the regulatory effects of miRNAs on cisplatin-induced inflammation in intestinal epithelial cells (IEC-6). Our results demonstrate that cisplatin significantly decreases cell viability while inducing interleukin-6 (IL-6) expression in a dose-dependent manner. Moreover, we observed that cisplatin activates the phosphorylation of p38 and ERK but does not activate JNK in IEC-6 cells. Using specific inhibitors of p38 and ERK, we confirmed their roles in regulating IL-6 expression. Through analysis of the miRNA database, we identified several miRNAs that potentially target IL-6. Notably, rno-let-7f-5p and rno-let-7g-5p showed significant downregulation following cisplatin treatment. Transfection mimics and inhibitors of rno-let-7f-5p and rno-let-7g-5p further confirmed their regulatory role in IL-6 expression. Importantly, inhibition of the p38 and ERK pathways attenuated the cisplatin-induced reduction of rno-let-7f-5p and rno-let-7g-5p levels, suggesting a potential regulatory link between MAPK signaling and miRNA expression. In conclusion, our findings support a model in which cisplatin promotes inflammation in intestinal epithelial cells by activating the p38 and ERK pathways and is associated with the suppression of rno-let-7f-5p and rno-let-7g-5p. These findings provide mechanistic rationale that may inform future efforts to mitigate cisplatin-associated gastrointestinal toxicity.