PIK3C3, also known as VPS34, is a lipid kinase that converts phosphatidylinositol (PtdIns) to phosphatidylinositol-3-phosphate (PtdIns3P), playing core roles in macroautophagy, endosomal transport, and nutrient sensing [3,4]. It is involved in multiple biological processes and diseases, and genetic models like KO/CKO mouse models are valuable for studying its functions.

In Sertoli cell-specific Pik3c3 knockout (cKO) mice, after one round of normal spermatogenesis, the mice became infertile with disrupted Sertoli cell polarity and impaired spermiogenesis. This was due to the accumulation of the F-actin negative regulator SCIN related to the failure of its degradation through the autophagy-lysosome pathway, and the reduced phosphorylation of HDAC6 affecting the F-actin cytoskeleton [2].

In adipocyte-specific Pik3c3/VPS34 deficiency mice, there were defects in adipocyte differentiation, survival, and function, resulting in reduced adipose tissue mass, altered blood lipid levels, fatty liver disease, diabetes, and defective body temperature control, mirroring lipodystrophy in patients [1].

In thymic epithelial cell (TEC)-specific Pik3c3/VPS34 knockout mice, it was found that Pik3c3/VPS34 facilitates the positive selection of CD4 but not CD8 T lineage cells through a mechanism independent of canonical autophagy, by altering vesicle trafficking in TECs to modulate lysosomal protease activity for CD4 T cell positive selection [5].

In mouse kidney, Pik3c3 inhibition in proximal tubule cells (RPTCs) significantly delayed EGF-stimulated EGFR degradation and the termination of EGFR signaling by impeding the lysosomal degradation of EGFR [6].

In conclusion, Pik3c3 is essential for maintaining normal physiological functions in multiple cell types. Model-based research, especially KO/CKO mouse models, has revealed its crucial roles in spermatogenesis, adipose tissue health, T-cell development, and renal cell physiology, providing insights into related disease mechanisms such as infertility, metabolic diseases, immune-related disorders, and kidney-related diseases.