Cathepsin K (CatK) is one of the most potent proteases in lysosomal cysteine proteases family, of which main function is to mediate bone resorption. Currently, CatK is among the most attractive targets for anti-osteoporosis drug development. Although many pharmaceutical companies are working on the development of selective inhibitors for CatK, there is no FDA approved drug till now. Odanacatib (ODN) developed by Merck & Co. is the only CatK inhibitor candidate which demonstrated high therapeutic efficacy in patients with postmenopausal osteoporosis in Phase III clinical trials. Unfortunately, the development of ODN was finally terminated due to the cardio-cerebrovascular adverse effects. Therefore, it arouses concerns on the undesirable CatK inhibition in non-bone sites. It is known that CatK has far-reaching actions throughout various organs besides bone. Many studies have also demonstrated the involvement of CatK in various diseases beyond the musculoskeletal system. This review not only summarized the functional roles of CatK in bone and beyond bone, but also discussed the potential relevance of the CatK action beyond bone to the adverse effects of inhibiting CatK in non-bone sites.

Mycomedicine is a unique class of natural medicine that has been widely used in Asian countries for thousands of years. Modern mycomedicine consists of fruiting bodies, spores, or other tissues of medicinal fungi, as well as bioactive components extracted from them, including polysaccharides and, triterpenoids, etc. Since the discovery of the famous fungal extract, penicillin, by Alexander Fleming in the late 19th century, researchers have realised the significant antibiotic and other medicinal values of fungal extracts. As medicinal fungi and fungal metabolites can induce apoptosis or autophagy, enhance the immune response, and reduce metastatic potential, several types of mushrooms, such as Ganoderma lucidum and Grifola frondosa, have been extensively investigated, and anti-cancer drugs have been developed from their extracts. Although some studies have highlighted the anti-cancer properties of a single, specific mushroom, only limited reviews have summarised diverse medicinal fungi as mycomedicine. In this review, we not only list the structures and functions of pharmaceutically active components isolated from mycomedicine, but also summarise the mechanisms underlying the potent bioactivities of several representative mushrooms in the Kingdom Fungi against various types of tumour.

Quiescent prostate cancer (PCa) cells that survive therapy can later reactivate and drive tumor recurrence and metastasis. Here, we identify a strategy to eliminate these cells during their vulnerable reactivation phase. We show that guttiferone K (GUTK), a bioactive compound isolated from Garcinia yunnanensis Hu, selectively eradicates reactivating quiescent PCa cells by inducing mitochondrial apoptosis through caspase activation and loss of mitochondrial membrane potential (ΔΨm). Mechanistically, GUTK suppresses Aurora A recovery and stabilizes SOD2 protein, thereby promoting mitochondrial dysfunction and apoptosis. SOD2 enhances, whereas Aurora A overexpression attenuates, GUTK-induced cell death. In orthotopic and xenograft prostate tumor models, GUTK combined with docetaxel significantly inhibits tumor growth and suppresses post-chemotherapy recurrence without evident toxicity. These findings identify GUTK as a potential therapeutic agent targeting reactivating quiescent PCa cells and highlight the Aurora A-SOD2 axis as a promising pathway for preventing PCa recurrence.