Bailly_2025_Life.(Basel)_15_

Highly degraded sterols belonging to the incisterol group have been identified in a large set of microorganisms. The leading product in the family is demethylincisterol A3 (DM-A3), isolated from various fungi and endowed with marked antitumor properties. Since the initial discovery of incisterol from a marine sponge in the 1990s, more than 30 incisterol-type natural products have been identified, essentially from fungi. An overview of these products, their bio-origin, chemical synthesis, and associated pharmacological properties is presented. The series includes diverse incisterol and demethylincisterol derivatives, chaxines, volemolide, different analogues (salimyxins, phellinignincisterols, daedatrin D, inonotoide F, aplykurodinone-1, dendrodoristerol), and a glycoside derivative (xyloneside), all bearing a tetracyclic incisterol framework. An analysis of the anticancer mechanism of the action of DM-A3 underlined the three main components of its activity associated with the (i) inhibition of beta-catenin and the Wnt signaling pathway, (ii) inhibition of tyrosine phosphatase SHP2 (IC(50) = 6.75 microM) implicated in cancer cell survival and differentiation, and (iii) blockade of alpha7nAchR activation coupled with inhibition of acetylcholinesterase (IC(50) = 11.16 microM). A comprehensive picture of the DM-A3 mechanism of action is discussed, highlighting the uniqueness of the compound as a dual SHP2/AchE inhibitor able to attenuate an inflammatory response through the cholinergic anti-inflammatory pathway. The review shed light on this little-known category of incisterol-type natural products, with the objective of promoting further research into this neglected group of anticancer agents.