At the molecular level, Nerandomilast elevated lung tissue cAMP levels, inhibited the phosphorylation of pro-survival/activation pathways (PI3K/AKT, NF-κB, STAT3) in B cells, and enhanced CREB phosphorylation.<h4>Conclusion</h4>The PDE4B inhibitor Nerandomilast demonstrates potent therapeutic effects in a preclinical IIM-ILD model, alleviating both myositis and pulmonary pathology. Here, CREB1 is linked to interstitial lung disease.