A systematic review of 46 structurally diverse terpenoids — spanning monoterpenoids, diterpenoids, triterpenoids, and sesquiterpenoids — reveals that most compounds simultaneously engage both autophagy and cellular senescence (CS) pathways in pulmonary cancer cells. Key mechanistic convergence points include AMPK, NF-κB, PI3K/AKT/mTOR, MAPK/ERK/JNK, ROS signaling, p53, Rb, and senescence-associated secretory phenotype (SASP) factors — suggesting these natural metabolites exploit shared regulatory architecture rather than isolated targets.
The finding matters because autophagy and cellular senescence occupy a genuinely paradoxical position in oncology: both can suppress or promote tumors depending on context, timing, and the tumor microenvironment. Terpenoids that simultaneously modulate both pathways could theoretically tip this balance toward tumor suppression — a strategy conventional cytotoxics rarely achieve. Compounds like ursolic acid, betulinic acid, and parthenolide have individually shown preclinical promise against lung cancer cell lines, and this framework helpfully organizes their mechanisms.
However, critical limitations constrain enthusiasm. This is a review, not a primary experimental study, synthesizing exclusively preclinical data. The bioavailability problem for terpenoids is well-documented and persistent — poor aqueous solubility and rapid hepatic metabolism have repeatedly stalled clinical translation. No human trial data are presented. The SASP angle is particularly underdeveloped; senescence-induced SASP can paradoxically fuel neighboring tumor cells, a nuance the review acknowledges but cannot resolve. Incremental rather than paradigm-shifting, this work serves best as a target-mapping resource for future drug delivery research.