Betulinic acid and apoptosis-involved pathways: Unveiling its bidirectional regulatory role

Betulinic acid (BA), a naturally occurring pentacyclic triterpenoid, exhibits remarkable bidirectional regulatory effects on apoptosis, demonstrating pro-apoptotic activity in cancer cells while protecting normal cells from oxidative stress and apoptosis. This systematic review synthesizes decade-long research to elucidate BA's multifaceted mechanisms across apoptosis-related pathways. In malignant cells, BA induces caspase-dependent apoptosis through both extrinsic pathways mediated by FADD via death receptor activation and intrinsic mechanisms involving ROS accumulation, Bcl-2 family-mediated mitochondrial dysfunction, and ERS-triggered PERK activation. Concurrently, it suppresses PI3K-Akt and NF-κB survival signaling while activating AMPK/mTOR-autophagy crosstalk and p53-dependent DNA damage responses. Paradoxically, BA protects normal tissues by enhancing antioxidant defenses through Nrf2/SOD activation, inhibiting pro-inflammatory TNF-α/NF-κB signaling, and stabilizing mitochondrial integrity. Key to its therapeutic potential is the context-dependent modulation of critical nodes that balance apoptosis initiation and cytoprotection. Structural derivatives and nano-formulations further enhance BA's tumor selectivity and bioavailability. By mapping BA's pleiotropic interactions within apoptotic networks, this review highlights its unique capacity to function as a precision therapeutic agent, offering dual cytostatic and cytoprotective benefits. These insights position BA as a promising candidate for cancer therapy development, warranting further investigation into pathway crosstalk and clinical translation strategies.