In contrast to the occupancy-driven pharmacology of classical inhibitors, proteolysis-targeting chimeras (PROTACs) represent a small molecule-based heterobifunctional tool with an event-driven mode of action (MoA). This catalytic MoA relies on hijacking the endogenous ubiquitination process in cells, thereby tagging the protein of interest (POI) for degradation by the proteasome. Consequently, PROTAC-induced degradation reduces cellular POI levels, offering potential therapeutic applications across various diseases. Several HDAC6-targeting PROTACs have been reported to date. Most of these PROTACs utilize hydroxamic acid-based HDAC6 ligands as warheads and recruit either cereblon (CRBN) or von Hippel-Lindau (VHL) as E3 ligases. Notably, these PROTACs exhibit potent HDAC6 degradation, with some achieving DC50 values in the low nanomolar range. Previous studies includes degraders based on HDAC6-selective inhibitors (e.g., nexturastat A), non-selective HDAC inhibitors (e.g., vorinostat), and HDAC6/8-selective inhibitors. In addition to the above-mentioned hydroxamic acid-based PROTACs, we reported the first non-hydroxamate selective HDAC6 degraders in 2022. These degraders employed a difluoromethyl-1,3,4-oxadiazole warhead as a zinc-binding group and engaged CRBN or VHL as E3 ligases. HDAC6 PROTACs have also been explored as potential therapeutic agents beyond cancer, including applications of a nexturastat A-based degrader in renal ischemia-reperfusion injury (RIRI) and a vorinostat-derived degrader in inflammation. However, none of these above-mentioned studies have examined the effects of HDAC6 PROTACs on HDAC10 protein levels, the other member of the class IIb HDAC family.