DNAJA1, also known as HDJ2, is a member of J-domain containing proteins or heat shock protein 40. It is involved in multiple cellular processes such as protein folding and degradation regulation. It interacts with other proteins and is associated with pathways related to cancer metastasis, metabolism, and spermatogenesis, playing an important role in various biological functions and disease-related processes. Genetic models, like knockout mice, are valuable for studying its functions [1-10].

In knockout mouse models, DNAJA1 knockout leads to complete infertility in male mice, as it is essential for spermatogenesis. DNAJA1 knockout also reduces protein polyubiquitination in the testis [3]. In human umbilical vein endothelial cells, DNAJA1-knockout alleviates heat stroke-induced endothelial barrier disruption by improving thermal tolerance and suppressing the MLCK-MLC signaling pathway [6]. In cancer-related studies, knockdown of DNAJA1 in head and neck squamous cell carcinoma (HNSCC) cell lines carrying unfolded mutant p53 (mutp53) decreases mutp53 levels, filopodia/lamellipodia formation, migratory potential, and active forms of CDC42/RAC1, and inhibits primary tumor growth and metastases to the lymph nodes and lungs. This indicates its role in promoting HNSCC metastasis in a mutp53-dependent manner [1]. In breast cancer, knockdown of DNAJA1 decreases cell proliferation, invasion, and metastasis both in vitro and in vivo, as it promotes these processes via the P53-R175H/NF-κB pathway [4]. In liver cancer, depletion of DNAJA1 in certain cell lines shows opposite effects on cell proliferation, invasion, and angiogenesis compared to overexpression, and in vivo it inhibits tumor growth and pulmonary metastasis [5]. In pancreatic ductal adenocarcinoma, DNAJA1 overexpression leads to mitochondrial fusion, an increase in Bcl-2 expression, and an anti-apoptotic phenotype [2].

In conclusion, DNAJA1 is essential for spermatogenesis and plays significant roles in various cancer-related processes such as metastasis and proliferation. Studies using knockout models have revealed its functions in these specific biological processes and disease conditions, highlighting its potential as a therapeutic target in cancer and its importance in male fertility research.