**6. Concluding Remarks**

Dysregulation of the ubiquitin–proteasome system including the positive or negative regulation of E3 ligases, DUBs, or proteasomes seriously a ffects cellular homeostasis and causes the development of serious pathologic conditions, such as tumor suppression or promotion in cancer, protein accumulation in neurodegenerative diseases, and forming an ine ffective immune response in the body (Figure 3). Thus, recently a grea<sup>t</sup> deal of work has been devoted to the development of novel drugs, targeting proteins that either interfere or inhibit ubiquitination and proteasome activity in disease-dependent manner. Ongoing research studies of a wide range of molecules targeting di fferent ligases show promising data in several pathogenic conditions; nevertheless, the translation of these data into clinical application is still a major challenge. For instance, some compounds are shown to inhibit E3 ligases generally in in vitro conditions, but the e ffects of such compounds remain unclear in in vivo models [193]. Proteasome-associated DUBs have been suggested as remarkable drug targets due to their lower side e ffects compared to proteasome-targeted drugs. Currently, DUBs-targeted inhibitors are mainly small molecules, and their development is still in the preclinical stage for inflammatory disease and cancer treatment [194]. The major restriction of DUBs inhibitors is their selectivity, as they may have complex intracellular interactions with several signaling pathways. Proteasome activity is another target in UPS-dependent therapy that became a popular idea to recover prominently in neurodegenerative diseases. Proteasome inhibitors, including bortezomib, carfilzomib, and ixazomib are well-tolerated by patients and therefore approved by the FDA for clinical applications. On the other hand, marizomib and oprozomib are currently under clinical trials [195]. In upcoming years, novel molecules targeting E3 ligases, DUBs, or proteasomes are expected to be validated for therapeutic approaches; thus, a better understanding of the molecular signaling pathways involved in ubiquitination and proteasomal degradation will allow the discovery of novel targeting molecules in cancer, neurodegenerative disease, and immune-related pathological conditions.

**Figure 3.** Summary of DUBs and E3 enzymes that play important roles in cancer progression, immune regulation, and neurodegenerative diseases. According to diseases, the enzymes positively or negatively regulate the mechanisms in mitophagy, cell differentiation, cell development, signaling, protein accumulation, neural malfunction, synaptogenesis, inhibition of apoptosis, cell cycle stimulation, mitochondrial regulation, autophagic flux, ER homeostasis, and protein degradation. E3 ligases and DUBs in the upside or downside of the semicircle indicate negative (red area) or positive regulators (green area) of these diseases.

**Author Contributions:** G.C., H.K., E.O.; original draft preparation, O.K., review, and editing. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
