Ism1, or Isthmin 1, is a secreted protein with diverse functions. It is involved in multiple biological processes such as inflammation regulation, metabolism, organ development, and immune response [1-10]. It participates in pathways like NF-κB, PI3K-AKT, and NODAL signaling, highlighting its importance in maintaining normal physiological functions and disease development [1,4,5]. Gene knockout (KO) mouse models have been crucial in understanding Ism1's functions.

In Ism1 -/- mice, intratracheal LPS challenge led to intensified acute lung inflammation with increased leukocyte infiltration and pro-inflammatory cytokines, and post-ALI fibrosis was enhanced, suggesting Ism1's role in suppressing LPS-induced acute lung injury and post-injury lung fibrosis likely via NF-κB pathway [1]. Absence of Ism1 in mice also led to increased alveolar macrophage number and functional heterogeneity, causing lung inflammation and emphysema similar to human COPD [2]. In early kidney development, Ism1-deficient mice showed defective ureteric bud bifurcation and impaired metanephric mesenchyme condensation due to compromised Gdnf/Ret signaling [3]. Ism1 ablation in mice resulted in impaired glucose tolerance, reduced adipose glucose uptake, and decreased insulin sensitivity [4].

In conclusion, Ism1 is a multi-functional protein. Through model-based research, especially KO mouse models, its roles in diseases such as acute lung injury, COPD, renal agenesis, and metabolic disorders have been revealed. Understanding Ism1 provides insights into disease mechanisms and potential therapeutic targets.