Triterpenoid saponins from Ilex latifolia inhibit breast cancer growth by disrupting the SREBP1/FASN-mediated lipid metabolic pathway
Year: 2025
Type: article
Abstract: Dysregulated lipid metabolism is a hallmark of breast cancer progression, with the SREBP-1/FASN axis serving as a key driver of tumor growth and survival. Natural products offer a valuable reservoir of metabolic modulators, yet their mechanisms and translational potential remain insufficiently defined. Here, we investigated the anti-breast cancer effects of Kundinoside D (KD-D), a triterpenoid saponin isolated from Ilex latifolia , and evaluated the in vivo efficacy of its bioactive extract fractions. In vitro, KD-D suppressed proliferation, induced apoptosis, and caused G1/G2 cell-cycle arrest in luminal (MCF-7) and triple-negative (MDA-MB-231) breast cancer cells. KD-D markedly downregulated SREBP-1 and FASN expression, as confirmed by Western blotting and immunofluorescence. Functional assays using siRNA-mediated knockdown and pharmacological inhibition of SREBP-1 enhanced KD- D -induced apoptosis, validating the functional significance of this pathway. Molecular docking predicted stable binding of KD-D to SREBP-1, which was experimentally supported by a cellular thermal shift assay demonstrating direct protein stabilization. Rescue experiments further showed that overexpression of constitutively active nuclear SREBP-1 partially restored cell viability and triglyceride synthesis following KD-D treatment. In vivo, oral administration of Ilex latifolia n-butanol and ethyl acetate fractions significantly suppressed MCF-7 xenograft growth, induced tumor necrosis, and reduced SREBP-1/FASN expression without causing weight loss. Collectively, these findings identify SREBP-1 as a direct molecular target of KD-D and demonstrate that Ilex latifolia -derived constituents exert potent antitumor effects through lipid metabolism inhibition, underscoring their potential as metabolism-targeted therapeutics for breast cancer. KD-D binds directly to SREBP-1, disrupting its transcriptional activation of FASN and downstream lipid biosynthesis. This novel KD-D/SREBP-1/FASN interaction suppresses breast cancer cell proliferation and tumor growth, highlighting a metabolism-targeted therapeutic strategy for breast cancer. ● Identification of Kundinoside D as a novel inhibitor of the SREBP-1/FASN lipid metabolic pathway. ● Demonstration that KD-D induces apoptosis and cell cycle arrest in luminal and triple-negative breast cancer models. ● KD-D directly binds and stabilizes SREBP-1, confirming specific metabolic target engagement. ● Functional and rescue assays validate SREBP-1 inhibition as the mechanism of KD-D cytotoxicity. ● Discovery of subtype-specific metabolic vulnerabilities, suggesting tailored therapeutic applications.
Source: Biomedicine & Pharmacotherapy
Authors: Fangfang Wang, Mingjie Wang, Zihan Shi, Yongchen Wu, Cunqin Wang, Hongting Wang
Institution: Wannan Medical College
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,610
OpenAlex ID: W4416660870