Lpar3-KO Mouse

Lpar3, short for Lysophosphatidic acid receptor 3, is coupled to Gαi/o and Gα11/q signaling. It is involved in multiple biological processes and associated with various pathways [3]. Lpar3 is important in cell proliferation, apoptosis, and disease development, and thus has overall biological significance in understanding normal and disease-related cellular functions [2]. Genetic models, such as knockout models, can be valuable in studying its functions.

In Ras-transformed cells, the knockout of Lpar3 in NIH 3T3 and Bhas 42 cells decreased cell survival, transformed foci, and colony formation. LPAR3 downregulation led to the robust accumulation of LC3-II and autophagosomes and inhibition of autophagic flux, suggesting that paradoxical downregulation of LPAR3 exerts cooperative tumor-promoting activity with MEK activation through autophagy induction in Ras-transformed cells [3].

In knee osteoarthritis (KOA), overexpression of LPAR3 in synovial fibroblast-like synoviocytes upregulated the expression of GPX4, Nrf2, and SOD1, while downregulating the expression of MMP13 and MMP3. In contrast, LPAR3 knockdown reversed these changes, indicating that LXA4 can inhibit FLSs ferroptosis by activating the ESR2/LPAR3/Nrf2 axis, alleviating KOA pain and pathological progression [1].

In nasopharyngeal carcinoma, matrix stiffness increases the expression of LPAR3, triggering epithelial-mesenchymal transition related to metastasis, and simultaneous inhibition of LPAR3 and COL8A1 genes significantly reduces nasopharyngeal carcinoma invasion and metastasis [4].

In conclusion, Lpar3 is crucial in processes like autophagy in cancer cells and ferroptosis in KOA-related cells, as well as in the metastasis of nasopharyngeal carcinoma. The use of gene knockout models in these studies has provided insights into its role in these disease areas, contributing to a better understanding of disease mechanisms and potentially offering new therapeutic targets.

References:

1. Hu, Zhehan, Chen, Liang, Zhao, Jihui, Shen, Peng, Yang, Yue. 2024. Lipoxin A4 ameliorates knee osteoarthritis progression in rats by antagonizing ferroptosis through activation of the ESR2/LPAR3/Nrf2 axis in synovial fibroblast-like synoviocytes. In Redox biology, 73, 103143. doi:10.1016/j.redox.2024.103143. https://pubmed.ncbi.nlm.nih.gov/38754271/

2. Yu, Hongde, Zhang, Bolun, Qi, Lin, Li, Jiaze, Meng, Qingtao. 2023. AP003352.1/miR-141-3p axis enhances the proliferation of osteosarcoma by LPAR3. In PeerJ, 11, e15937. doi:10.7717/peerj.15937. https://pubmed.ncbi.nlm.nih.gov/37727685/

3. Hwang, Sung-Hee, Kim, Hye-Gyo, Lee, Michael. 2022. Paradoxical downregulation of LPAR3 exerts tumor-promoting activity through autophagy induction in Ras-transformed cells. In BMC cancer, 22, 969. doi:10.1186/s12885-022-10053-0. https://pubmed.ncbi.nlm.nih.gov/36088312/

4. Yi, Lu, Xie, Haijing, Zhang, Xin, You, Yiwen, You, Bo. 2025. LPAR3 and COL8A1, as matrix stiffness-related biomarkers, promote nasopharyngeal carcinoma metastasis by triggering EMT and angiogenesis. In Cellular signalling, 131, 111712. doi:10.1016/j.cellsig.2025.111712. https://pubmed.ncbi.nlm.nih.gov/40049264/