HSPA1L, a member of the 70kD heat shock protein (Hsp70) family, is an evolutionarily conserved gene. It functions as a molecular chaperone and is involved in various biological processes. HSPA1L has been associated with pathways like the HSPA1L-Parkin pathway related to mitophagy [1]. It also plays roles in processes such as epithelial-mesenchymal transition (EMT), cancer stem cell-like properties regulation, and is involved in maintaining organellar function in proximal tubular cells [3,5].

In male mice, Hspa1l -/- generated by the Nuclease technology system exhibited normal development and fertility, indicating that HSPA1L is not essential for physiological spermatogenesis nor involved in heat-induced stress responses [6]. In diabetic sarcopenia, MFG-E8 was found to interact with HSPA1L, and the HSPA1L-Parkin pathway was involved in mitophagy regulation [1]. In preeclampsia, the HSPA1L rs1061581 polymorphism was associated with the risk of the disease in Han Chinese women [2]. In idiopathic male infertility in the Iranian population, the HSPA1L rs2227956 polymorphism was associated with susceptibility to the disease [4]. In non-small cell lung cancer, HSPA1L enhanced CSC-like properties by activating IGF1Rβ and regulating β-catenin transcription [3]. In diabetic kidney disease, a vaspin-HSPA1L complex protected proximal tubular cells from organelle stress [5]. In hypertensive nephropathy, VEGFR3 regulated the crotonylation of HSPA1L to enhance mitophagy [7].

In summary, HSPA1L is involved in multiple biological functions including mitophagy, spermatogenesis-related processes, and cancer-associated mechanisms. The use of gene knockout mouse models, like the Hspa1l -/- mice, has provided insights into its non-essential role in spermatogenesis. In disease areas such as preeclampsia, idiopathic male infertility, diabetic sarcopenia, diabetic kidney disease, and hypertensive nephropathy, HSPA1L has been linked to disease susceptibility or pathogenesis, highlighting its significance in understanding these conditions.

References:

1. Zhao, Wenqian, Zhao, Bin, Meng, Xinyue, Gao, Haiqing, Cheng, Mei. 2024. The regulation of MFG-E8 on the mitophagy in diabetic sarcopenia via the HSPA1L-Parkin pathway and the effect of D-pinitol. In Journal of cachexia, sarcopenia and muscle, 15, 934-948. doi:10.1002/jcsm.13459. https://pubmed.ncbi.nlm.nih.gov/38553831/

2. Zong, Jinbao, Lin, Yan, Tian, Qingwu, Sun, Guirong, Liu, Shiguo. . HSPA1L rs1061581 polymorphism is associated with the risk of preeclampsia in Han Chinese women. In Bioscience reports, 40, . doi:10.1042/BSR20194307. https://pubmed.ncbi.nlm.nih.gov/32039449/

3. Choi, Soo-Im, Lee, Jei-Ha, Kim, Rae-Kwon, Cho, Eun-Wie, Kim, In-Gyu. 2020. HSPA1L Enhances Cancer Stem Cell-Like Properties by Activating IGF1Rβ and Regulating β-Catenin Transcription. In International journal of molecular sciences, 21, . doi:10.3390/ijms21186957. https://pubmed.ncbi.nlm.nih.gov/32971893/

4. Kohan, Leila, Tabiee, Omid, Sepahi, Neda. 2019. HSPA1L and HSPA1B gene polymorphisms and haplotypes are associated with idiopathic male infertility in Iranian population. In European journal of obstetrics, gynecology, and reproductive biology, 240, 57-61. doi:10.1016/j.ejogrb.2019.06.014. https://pubmed.ncbi.nlm.nih.gov/31228677/

5. Nakatsuka, Atsuko, Yamaguchi, Satoshi, Eguchi, Jun, Sugiyama, Hitoshi, Wada, Jun. 2021. A Vaspin-HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease. In Communications biology, 4, 373. doi:10.1038/s42003-021-01902-y. https://pubmed.ncbi.nlm.nih.gov/33742129/

6. Wang, Xin, Xie, Wenxiu, Yao, Yejin, Zhou, Zuomin, Liu, Mingxi. 2020. The heat shock protein family gene Hspa1l in male mice is dispensable for fertility. In PeerJ, 8, e8702. doi:10.7717/peerj.8702. https://pubmed.ncbi.nlm.nih.gov/32231871/

7. Wu, Qiuwen, Fu, Jiaxin, Zhu, Bin, Peng, Cong, Zhang, Shuo. 2025. VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L. In Cell communication and signaling : CCS, 23, 52. doi:10.1186/s12964-025-02045-x. https://pubmed.ncbi.nlm.nih.gov/39875989/