Slc12a5, encoding K+-Cl- cotransporter 2 (KCC2), is the main Cl- extruder of neurons. It enables the proper inhibitory function of neurotransmitters like γ-aminobutyric acid (GABA) and glycine, thus maintaining the excitation-inhibition balance in the nervous system. Post-translational modifications such as phosphorylation and glycosylation regulate KCC2 functions [1].

Loss-of-function variants of human SLC12A5 have pathogenic potential, as they can disrupt the Cl- transporting activity of KCC2, which may lead to neurological and psychiatric disorders [1]. In glioblastoma multiforme (GBM), SLC12A5 shows promise as a novel biomarker, being deficient in GBM but enriched in normal neural tissues, and its overexpression inhibits GBM cell proliferation [2]. In hepatocellular carcinoma (HCC), high SLC12A5 expression promotes tumor growth and ferroptosis resistance by inducing ER stress and changing cystine transport [3]. In bladder urothelial carcinoma, SLC12A5 promotes tumor progression by interacting with and stabilizing SOX18, then upregulating MMP7 [4]. In breast cancer, ETV4-mediated transcriptional activation of SLC12A5 exacerbates ferroptosis resistance and glucose metabolism reprogramming [5]. In prostate cancer, SLC12A5 functions as an oncogene to promote tumor progression and castration resistance through YTHDC1 and HOXB13 [6]. In ovarian carcinoma, overexpression of SLC12A5 is associated with tumor progression and poor survival [7].

In conclusion, Slc12a5 plays a crucial role in maintaining the normal inhibitory function of neurons. Its dysregulation is associated with various cancers, including GBM, HCC, bladder, breast, prostate, and ovarian carcinomas. Research on Slc12a5, especially through gene-knockout or conditional-knockout mouse models (not directly mentioned in the references but relevant for further functional studies), could provide more insights into its functions and its roles in disease, potentially leading to new therapeutic strategies for these disorders.