CALML5 (calmodulin-like 5) is a calcium-binding protein primarily known for its role in epidermal differentiation and stratified epithelial tissue homeostasis. In normal physiology, CALML5 is transcriptionally regulated by ZNF750 and stabilized by the long noncoding RNA TINCR, functioning as a key component of epidermal barrier development 1. The protein interacts with stratifin (SFN) in suprabasal epidermis to regulate late-stage differentiation genes and keratohyalin granule formation 1. CALML5 knockout impairs epidermal differentiation and disrupts barrier function 1. In cancer biology, CALML5 acts as a tumor suppressor, with expression progressively lost during carcinogenesis. In cervical squamous cell carcinoma, CALML5 silencing occurs via disrupted KLF4 nuclear translocation through ERK signaling dysregulation, and its knockdown accelerates cell motility 2. In HER2+/HR+ breast cancer, CALML5 expression serves as a risk factor associated with drug resistance 3. The protein undergoes K63-linked ubiquitination specifically in nuclear fractions of premenopausal breast cancer patients, suggesting post-translational regulation in carcinogenesis 4. Beyond cancer, CALML5 emerges as a prognostic marker in hepatocellular carcinoma and thymic squamous cell carcinoma, with diagnostic sensitivity of 73.1% and specificity of 94.7% for thymic carcinoma differentiation 5. CALML5 additionally shows potential as a biomarker in silicosis, with combined cytokine-CALML5 assessment achieving 90% diagnostic accuracy 6.