Ism1, or Isthmin 1, is a secreted protein with diverse functions. It has been implicated in multiple biological processes and associated pathways. For instance, it may regulate NODAL signaling during development [5]. It is also recognized as an adipokine, playing roles in glucose and lipid metabolism [4,6,7]. Genetic models, such as gene knockout mouse models, have been crucial for studying its functions.

In Ism1 -/- mice, intratracheal LPS challenge led to intensified acute lung inflammation, with increased leukocyte infiltration and pro-inflammatory cytokines/chemokines, and subsequent enhanced post-ALI fibrosis [1]. Ism1 deficiency in mice also caused increased alveolar macrophage number and functional heterogeneity, resulting in lung inflammation, emphysema, and lung function decline, phenotypes similar to human COPD [2]. In early kidney development, Ism1 -/- mice exhibited defective ureteric bud bifurcation and impaired metanephric mesenchyme condensation due to compromised Gdnf/Ret signaling, ultimately leading to renal agenesis and hypoplasia/dysplasia [3]. Additionally, Ism1 ablation in mice led to impaired glucose tolerance, reduced adipose glucose uptake, and reduced insulin sensitivity [4].

In conclusion, Ism1 plays essential roles in maintaining lung homeostasis, regulating early kidney development, and modulating glucose metabolism. Studies using Ism1 knockout mouse models have significantly advanced our understanding of its functions in diseases such as acute lung injury, COPD, kidney developmental disorders, and diabetes-related metabolic diseases.