Tissue-specific molecular responses to salinomycin and their modulation by ionophore-antibiotic interactions in...

Salinomycin (SAL) is a widely used ionophore with a narrow safety margin, and its interactions with co-administered drugs may modulate toxicity, especially in susceptible species such as turkeys. Yet, the molecular mechanisms underlying these interactions in turkeys are not fully understood. This study aimed to characterize tissue-specific transcriptional responses to SAL and to evaluate how co-exposure with monensin (MON), enrofloxacin (ENR), and tiamulin (TIAM) modulates these effects. Using a hypothesis-driven RT-qPCR approach based on prior transcriptomic findings, we assessed the expression of genes related to cell-cycle regulation, mitochondrial function, inflammatory signaling, and xenobiotic metabolism in turkey heart and liver tissues. SAL induced non-linear and tissue-specific transcriptional responses, and the heart was the most affected tissue. In the heart, SAL affected genes associated with stress signaling, cell-cycle, and mitochondrial function, whereas in liver, responses were limited. Co-administration with MON, ENR, and TIAM attenuated SAL-induced transcriptional responses in the heart, indicating interaction-dependent modulation. Triple co-exposure (MON+ENR+SAL) caused more pronounced suppression of transcriptional activity and extended effects to mitochondrial-related pathways in both tissues. These findings demonstrate that the heart is the primary target of SAL toxicity in turkeys. Furthermore, ionophore-antibiotic interactions significantly modulate SAL-induced molecular responses in a treatment-dependent manner. This study provides mechanistic insight into drug-drug interactions in poultry and highlights candidate biomarkers for monitoring toxicity in poultry.