HS1BP3 is a multifunctional PX domain protein that regulates apoptosis, autophagy, and cell proliferation through distinct mechanisms. As an HS1-binding protein, HS1BP3 modulates lymphocyte signaling 1 and overexpression of HS1BP3 induces apoptosis in HEK293T and HeLa cells through HS1-dependent pathways, characterized by PARP cleavage and AP-1 transcriptional activation 2. HS1BP3 negatively regulates autophagosome formation by inhibiting PLD1 activity and localization to ATG16L1-positive membranes, thereby reducing phosphatidic acid content at autophagosome precursor sites [PMID:28004827; 34]. In hepatocellular carcinoma, HS1BP3 promotes tumor progression and is transcriptionally regulated by estrogen receptor 1 (ESR1); silencing HS1BP3 inhibits HCC cell proliferation and migration while promoting apoptosis 4. Additionally, HS1BP3 expression levels discriminate radiotherapy responders from non-responders in rectal cancer, suggesting roles in DNA damage response and autophagy-related processes 5. These findings establish HS1BP3 as a critical regulator of cell survival decisions with implications for cancer progression and therapeutic resistance.