Abstract / Summary
Celastrol, a quinone methide pentacyclic triterpenoid obtained mainly from the roots of Tripterygium wilfordii Hook. f., forms covalent, often reversible, adducts with cysteine thiols in regulatory proteins, which underlies its multi-targeted action. This review summarises the preclinical evidence on celastrol and its derivatives in breast, ovarian, and cervical cancer and the nanocarriers designed to overcome its pharmacological limitations. Chemoproteomics has defined covalent targets at three distinguishable levels of evidence: residue-mapped and confirmed by mutagenesis or by genetic validation for IKKβ, PRDX1, PKM2, HMGB1, and COMMD3; binding measured without mapping of the residue for the Hsp90–Cdc37 complex, the proteasome, further peroxiredoxins, and mitochondrial isocitrate dehydrogenases; and inferred from functional or degradation readouts for the remainder. Almost all of this work was performed outside the three tumour types, so the target catalogue applies to them by extrapolation. Across in vitro and in vivo models it induces cell-cycle arrest, apoptosis, and oxidative and mitochondrial stress, modulates NF-κB, PI3K/Akt/mTOR, JAK/STAT3, MAPK, Wnt/β-catenin, and Hippo signalling, and limits migration, invasion, and angiogenesis. It also engages paraptosis, endoplasmic reticulum stress, pyroptosis, ferroptosis, cuproptosis, and immunogenic cell death, and remodels the tumour immune microenvironment. Modification at the C-20 carboxyl group and the A/B ring system, including proteolysis-targeting chimeras, has improved potency and selectivity. Because solubility, oral bioavailability, and the therapeutic window remain limiting, liposomal, micellar, carrier-free, and biomimetic nanocarriers have been developed to improve tumour selectivity and safety. Translation will depend on optimised derivatives, advanced delivery, sustainable production, rigorous pharmacokinetic and toxicological evaluation, and the pharmacoeconomic considerations examined here.