Plant‐Based α‐Linolenic Acid as a Superior Nutraceutical to Modulates Apoptosis, Hypoxic Signaling, and Lipid Metabolic Pathway in Breast Cancer: A Comparative Preclinical Study

In this study, we investigated and compared the anticarcinogenic efficacy of plant‐derived α‐linolenic acid (P‐ALA) and marine‐derived α‐linolenic acid (M‐ALA) using MCF‐7 breast cancer cell line and mammary gland carcinoma model induced by N‐methyl‐N‐nitrosourea (MNU). In vitro MTT assessment on ER+ MCF‐7 cells exhibited significant cell viability with P‐ALA (IC 50 5.57 µM) when compared with M‐ALA (IC 50 5.91 µM) and tamoxifen (TAM) (IC 50 9.16 µM). Mitochondrial‐mediated apoptosis with apoptotic changes were more evident after P‐ALA treatment when scrutinized using DAPI, JC‐1, and AO/EtBr staining. The P‐ALA ( p > 0.001***) and M‐ALA ( p > 0.001***) reversed the cachexia associated with MNU and positively restored lipid profiles (↓TG, ↓LDL, ↓VLDL, and ↑HDL) ( p > 0.001***). ECG and HRV analysis showed that P‐ALA‐HD effectively restored autonomic functions. Lactate analysis P‐ALA‐HD significantly reduced lactate accumulation. Immunoblotting indicated upregulation of pro‐apoptotic (BAX; BAD and caspase‐3 at p > 0.001***) and down‐regulation of Bcl‐2 ( p > 0.001***). P‐ALA also inhibited lipogenesis (↓SREBP‐1c and FASN↑; p > 0.001***), glucose and lactate transport (GLUT‐1↓, MCT‐1 ↓, and MCT‐4↓ at p > 0.001***), hypoxic signaling (↓HIF‐1α p > 0.001*** and ↑PHD2 p > 0.001***), and intrinsic mitochondrial apoptotic marker (VDAC‐1↓ p > 0.001***). P‐ALA demonstrated anticancer, lipid‐modulating, and cardioprotective that underscore the potential of P‐ALA as efficacious and sustainable therapeutic approach for management of breast cancer.