Fentanyl-induced cortical and cardiopulmonary damage linked to immune response functions and apoptosis-necrosis networks in a multi-omics mouse model

Introduction Fentanyl can rapidly impair brain and cardiopulmonary functions due to its high pharmacokinetics, necessitating a systems-level investigation to elucidate the early host response profile. To address this, we developed an SKH-1 mouse model to integrate ex-vivo imaging with multi-omics data, enabling a comprehensive understanding of tissue-specific host responses across time and dose gradients. Methods Our previous study characterized the phenotypes of this mouse model to establish dose gradients and time points associated with major clinical manifestations. Building on these findings, cortex, heart, and lung tissues were collected postmortem at 40 min, 6h, 24h, and 7 days following administration of one of three fentanyl doses: the highest non-lethal dose (HNLD), LD10, and LD50. Results Multi-omics analysis revealed immune response networks and apoptosis-necrosis functions as primary targets of fentanyl. Cortical and pulmonary immune responses exhibited dose-dependent latencies but remained activated 7 days post-exposure, whereas the cardiac immune response was suppressed over time. Pulmonary apoptosis-necrosis was rapidly activated, contrasting with its delayed, dose-dependent activation in the heart. In the cortex, apoptosis-necrosis followed a monophasic longitudinal trajectory, with delayed activation after 24h followed by regression. These findings suggest tissue-specific time windows for early intervention. Subsequent machine learning analysis identified phylogenetically conserved and miRNAs, such as miR-146-5p and miR-877-3p, which demonstrated consistent time- and dose-independent regulation in the lungs and cortex, respectively. Conclusion Functional associations of these miRNAs with tissue-specific lesions highlight their potential therapeutic value. Further interrogation of miRNA-mRNA interactions and downstream target analysis could pave the way for developing precision countermeasures against fentanyl toxicity.