Triple-negative breast cancer (TNBC) is a malignant breast cancer. There is an urgent need for effective drugs to be developed for TNBC. Tubocapsicum anomalum (T. anomalum) has been reported to have an anti-tumor effect, and six novel withanolides were isolated from it and designated as TAMEWs. However, its anti-TNBC effect is still unknown. The results of an MTT assay indicated a higher sensitivity of TNBC cells to TAMEWs compared to other cells. TAMEWs induced apoptosis via mitochondrial dysfunction. They caused increased levels of lipid ROS and Fe²⁺, with downregulation of GSH and cystine uptake, and it has been confirmed that TAMEWs induced ferroptosis. Additionally, the results of Western blotting indicate that TAMEWs significantly decrease the expressions of ferroptosis-related proteins. Through further investigation, it was found that the knockdown of the p53 gene resulted in a significant reversal of ferroptosis and the expressions of its associated proteins SLC7A11, ASCT2, and GPX4. In vivo, TAMEWs suppressed TNBC growth with no obvious damage. The IHC results also showed that TAMEWs induced apoptosis and ferroptosis in vivo. Our findings provide the first evidence that TAMEWs suppress TNBC growth through apoptosis and ferroptosis.

Background: Chronic exposure to ultraviolet (UV) radiation, particularly UVB, is the primary driver of skin photoaging. Ferro-aging, a recently identified iron-triggered, lipid peroxidation-driven cellular senescence program distinct from acute ferroptotic cell death, has emerged as a critical contributor to age-related pathologies, yet its role in skin photoaging remains largely unexplored. Methods: In this study, we systematically evaluated the anti-photoaging efficacy of L-malate (LM), a naturally occurring organic acid, using both in vitro human skin cell models (HaCaT keratinocytes and HSFs) and an in vivo BALB/c nude mouse model of chronic UV irradiation. Results: Our results demonstrate that LM treatment significantly attenuated UVB-induced cellular senescence, DNA damage, and extracellular matrix remodeling in a dose-dependent manner. Mechanistically, LM may act by increasing the expression of malic enzymes (ME1 and ME2), thereby restoring intracellular NADPH levels and glutathione homeostasis. This metabolic restoration effectively blocks the ferro-aging cascade, as evidenced by suppressed ACSL4 upregulation, the maintenance of GPX4 protein levels, and reduced lipid peroxidation. Importantly, topical application of LM in UV-irradiated mice significantly ameliorated in vivo photoaging phenotypes and suppressed ferro-aging markers. Conclusions: In summary, our findings demonstrate that LM may inhibit ferro-aging through the ME1/ME2-NADPH antioxidant axis. This study reveals the possibility of ferro-aging as a potential novel therapeutic target in skin photoaging and suggests that LM is a promising naturally derived ferro-aging inhibitor with translational potential in anti-aging skincare.