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Mycoplasma pneumonia (MP), as a global infectious disease in sheep, seriously affects the production performance of sheep and economic benefits of sheep industry. However, current research on sheep resistance to MP remains limited. To address this gap and explore the potential epigenetic regulation of sheep MP resistant, this study employed high-throughput sequencing techniques (ATAC-Seq and CUT&Tag) to analyze epigenetic modifications in lung tissue from healthy and MP-affected sheep and reveal differential epigenetic landscapes associated with disease resistance. Integrating transcriptome analysis related to MP and genome-wide association studies (GWAS), FOXF1 was identified as a candidate gene for MP-resistance in sheep. We established a Mycoplasma ovipneumoniae (MO)-infected sheep alveolar epithelial cell model and regulated FOXF1 expression in cells through interference and overexpression techniques to study MO's adhesion and damage. The results showed that activation promoters or enhancer elements in FOXF1 introns of healthy lungs may enhance its transcription. FOXF1 overexpression reduced MO-mediated adhesion damage to cells, while knock-down increased it. Our work has enriched the gene pool for anti-pneumonia and studied the role of the FOXF1 gene in MO-infected cells, accumulating reliable genetic resources for sheep MP disease resistant breeding.