Stub1, also known as STIP1 homology and U-box-containing protein 1, encodes the CHIP (carboxyl terminus of Hsc70-interacting protein), an essential E3 ligase crucial for protein quality control. It functions as a co-chaperone for heat shock protein (HSP) via its N-terminal tetratricopeptide repeat (TPR) domain and as an E3 ligase, ubiquitinating substrates through its C-terminal U-box domain. Stub1 is involved in various physiological processes such as aging, autophagy, and bone remodeling, and has emerged as a key player in cancer and immunity [1].

In autophagy, STUB1-deficient cells and tissues from STUB1-deficient mice show reduced TFEB activity due to the accumulation of phosphorylated TFEB, leading to decreased autophagy and mitochondrial biogenesis. This indicates that STUB1 modulates TFEB-induced autophagy-lysosome pathway by targeting inactive phosphorylated TFEB for degradation [2].

In hepatocellular carcinoma, HSP90β impedes STUB1-induced ubiquitination of YTHDF2, driving sorafenib resistance [3].

In gastrointestinal stromal tumors, knocking down STUB1 reverses imatinib-induced ferroptosis, suggesting STUB1 promotes ferroptosis by mediating GPX4 ubiquitination [4].

In ovarian cancer, STUB1 suppresses paclitaxel resistance by mediating HOXB3 ubiquitination to inhibit PARK7 expression [5].

In conclusion, Stub1 plays essential roles in multiple biological processes. Through gene knockout or conditional knockout mouse models and other loss-of-function experiments, its functions in autophagy, tumor-related drug resistance, and ferroptosis have been revealed. These findings suggest Stub1 could be a potential therapeutic target in cancer and other diseases.