CLIC4, or Chloride intracellular channel 4, is a multifunctional protein. It is involved in diverse biological processes beyond its role as a putative chloride channel for intracellular organelles. It participates in pathways such as TGF-β signaling, endosomal trafficking, and is crucial for normal cellular homeostasis [2,4]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In a RPE-specific Clic4 knockout mouse model, it exhibits hallmarks of dry age-related macular degeneration, suggesting a link between CLIC4 and aberrant lipid metabolism and drusen formation [1]. In MAMs of cardiomyocytes, loss of CLIC4 in a murine model increased myocardial infarction and reduced cardiac function after IR injury, indicating its role in modulating ER and mitochondrial calcium homeostasis [3]. In two murine metastatic breast cancer models, constitutive ablation of host Clic4 nearly eliminated lung metastases without reducing primary tumor weight, showing that CLIC4 is required for host metastatic competence [5].

In conclusion, CLIC4 plays essential roles in various biological processes and disease conditions. Model-based research, especially KO/CKO mouse models, has revealed its significance in diseases like dry age-related macular degeneration, myocardial IR injury, and breast cancer metastasis, providing insights into potential therapeutic targets.