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. 2025 Apr 19;38(3):92.
doi: 10.1007/s13577-025-01219-6.

Hyaluronic acid-modified milk exosomes carrying ZNF516 inhibit ABCC5 and contribute to pemetrexed sensitivity in lung adenocarcinoma

Hui Li #  1 , Yanyan Sun #  2 , Jue Wang  2 , Zhiwu Wang  3 , Lan Wu  4 , Jie Lei  5 , Ying Gao  4
Affiliations

Hyaluronic acid-modified milk exosomes carrying ZNF516 inhibit ABCC5 and contribute to pemetrexed sensitivity in lung adenocarcinoma

Hui Li et al. Hum Cell. .

Abstract

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Milk-derived exosomes (mEXOs) have critical roles in cancer treatment. This paper explores the effects of hyaluronic acid (HA)-modified mEXOs (HA-mEXOs) in LUAD. HA-mEXOs were isolated and prepared, and PMX-resistant cells were developed. CCK-8, colony formation, Transwell, flow apoptosis, xenograft tumor assay, immunohistochemistry, and TUNEL experiments were conducted to explore the impact of mEXOs and HA-mEXOs on malignant behaviors and PMX sensitivity. The role of ZNF516 and ABCC5 on malignant behaviors and PMX sensitivity was investigated by shRNA lentiviral infection. HA modification increased the uptake and affinity of LUAD cells for mEXOs. mEXOs induced PMX-resistant LUAD cell sensitivity and inhibited their malignant behaviors. mEXOs enhanced PMX sensitivity and inhibited tumor growth. HA-mEXOs had superior effects to mEXOs. ZNF516 was lowered in LUAD-resistant cells and upregulated by mEXOs. ZNF516 bound to the ABCC5 promoter and repressed its transcriptional activation. The combined knockdown of ZNF516 reversed the antitumor benefits of mEXOs. HA-mEXOs-carrying ZNF516 enhance ZNF516 levels in LUAD/PMX cells and repress ABCC5, which in turn induces cell sensitivity to PMX and inhibits LUAD progression.

Keywords: ABCC5; Hyaluronic acid; Lung adenocarcinoma; Milk-derived exosomes; Pemetrexed resistance; ZNF516.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: All procedures involving animals were approved by the Animal Ethics Committee of Inner Mongolia Autonomous Region People’s Hospital, which is in agreement with the Guidance for Care and Use of Laboratory Animals. Consent to participate: Not applicable. Consent to publication: Not applicable.

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