A recent study published in Current Molecular Pharmacology reveals that gramine, a natural indole alkaloid derived from plants, exerts potent anti‑tumor effects against triple‑negative breast cancer (TNBC) by inducing ferroptosis through a previously unrecognized CUL3‑MTDH regulatory mechanism. TNBC remains the most aggressive breast cancer subtype with limited targeted therapies and frequent chemoresistance, highlighting an urgent need for novel treatment strategies.
The research team, led by corresponding author Yuanliang Yan from Xiangya Hospital, Central South University, screened 27 indole alkaloids and identified gramine as the most promising candidate with selective cytotoxicity toward TNBC cells (IC₅₀ ~22–28 μM) while sparing normal mammary epithelial cells. Through comprehensive proteomic analysis, molecular docking, and biochemical assays, the investigators demonstrated that gramine directly binds to Cullin 3 (CUL3), a scaffold protein of E3 ubiquitin ligase complexes. This binding reduces CUL3‑mediated ubiquitination and subsequent proteasomal degradation of metadherin (MTDH), leading to MTDH protein stabilization.
Mechanistically, MTDH upregulation by gramine suppresses the expression of ferroptosis inhibitors SLC3A2 and GPX4, while promoting hallmark ferroptotic events including increased intracellular iron (Fe²⁺), reactive oxygen species (ROS), malondialdehyde (MDA), and depleted glutathione (GSH), along with characteristic mitochondrial morphological changes. "Our findings establish the CUL3‑MTDH‑ferroptosis axis as a novel regulatory pathway and provide a mechanistic basis for developing natural compound‑based therapeutics that target ferroptosis in TNBC," Dr. Yan stated.
In vivo experiments using 4T1 syngeneic and MDA‑MB‑231 xenograft mouse models confirmed that gramine significantly suppressed tumor growth at doses of 10 and 20 mg/kg without observable systemic toxicity or body weight loss. Importantly, genetic knockdown of MTDH or pharmacological inhibition of ferroptosis effectively reversed gramine's antitumor effects, confirming the mechanistic pathway. "This study not only identifies gramine as a potent natural anti‑cancer agent but also uncovers a new therapeutic rationale for targeting the CUL3‑MTDH axis in TNBC," added co‑author Keda Yu from Fudan University Shanghai Cancer Center.
The researchers suggest that gramine may hold particular promise for overcoming drug resistance in TNBC and could potentially synergize with immunotherapies. Future investigations will focus on elucidating gramine's metabolic fate, bioavailability, and immunomodulatory effects, as well as exploring combination strategies with existing therapeutic modalities.
Click here to read the full article: https://doi.org/10.1016/j.cmp.2026.03.001
Current Molecular Pharmacology