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Hsa_piR_016975是纳米疗法的一个新靶点，它通过减弱Maspin/谷胱甘肽过氧化物酶4介导的铁死亡来促进肝癌进展和索拉非尼耐药。

Hsa_piR_016975 Is a Novel Target of Nanotherapy that Boosts Hepatoma Progression and Sorafenib Resistance by Abating Maspin/GPX4-Mediated Ferroptosis.

作者信息

Feng Wei, Xu Jing, Chen Bairong, Liu Jibin, Hu Yuhao, Cao Xuemin, Qi Jing, Ju Linling, Shao Jianguo, Dong Peixin, Chen Lin, Wang Feng

机构信息

Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.

Institute of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong 226631, Jiangsu, China.

出版信息

Biomater Res. 2025 Jul 2;29:0225. doi: 10.34133/bmr.0225. eCollection 2025.

DOI:10.34133/bmr.0225
PMID:40606680
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12218766/
Abstract

PIWI-interacting RNAs (piRNAs) are known to be involved in germline development, but their potential mechanisms in carcinogenesis remain elusive. Herein, we investigated the roles of hsa_piR_016975, a novel piRNA, in hepatocellular carcinoma (HCC) progression and its therapeutic effects on drug resistance to sorafenib. The results disclosed that hsa_piR_016975 was highly expressed in HCC and promoted HCC growth, metastasis, epithelial mesenchymal transition (EMT) formation, and sorafenib resistance. Mechanistic research uncovered that hsa_piR_016975 could target inhibition of the expression of serpin family B member 5 (SERPINB5; also known as Maspin) while up-regulating glutathione peroxidase 4 (GPX4) expression, thereby attenuating the ferroptosis and resulting in HCC progression and drug resistance. Furthermore, a novel delivery system was constructed, which was encapsulated with sorafenib and hsa_piR_016975 inhibitor in the nanoparticles of polylactic-co-glycolic acid and subsequently coated with the HCC cell membrane (namely, in-016975/Sora@PLGA-CM). The nanocomposites could effectively reverse HCC progression and sorafenib resistance by inducing hsa_piR_016975/Maspin/gpx4 axis-mediated ferroptosis in both subcutaneous xenograft model and orthotopic transplantation model. Overall, this study illuminates the critical role and molecular mechanisms of hsa_piR_016975 in hepatocarcinogenesis and provides a promising piRNA-oriented nanodelivery strategy for overcoming sorafenib resistance in HCC.

摘要

已知PIWI相互作用RNA（piRNA）参与生殖细胞发育，但其在致癌过程中的潜在机制仍不清楚。在此，我们研究了一种新型piRNA——hsa_piR_016975在肝细胞癌（HCC）进展中的作用及其对索拉非尼耐药性的治疗效果。结果显示，hsa_piR_016975在HCC中高表达，并促进HCC生长、转移、上皮-间质转化（EMT）形成和对索拉非尼的耐药性。机制研究发现，hsa_piR_016975可靶向抑制丝氨酸蛋白酶抑制剂家族B成员5（SERPINB5；也称为Maspin）的表达，同时上调谷胱甘肽过氧化物酶4（GPX4）的表达，从而减弱铁死亡，导致HCC进展和耐药。此外，构建了一种新型递送系统，将索拉非尼和hsa_piR_016975抑制剂封装在聚乳酸-乙醇酸共聚物纳米颗粒中，随后用HCC细胞膜包被（即in-016975/Sora@PLGA-CM）。该纳米复合材料可通过诱导hsa_piR_016975/Maspin/gpx4轴介导的铁死亡，在皮下异种移植模型和原位移植模型中有效逆转HCC进展和索拉非尼耐药性。总体而言，本研究阐明了hsa_piR_016975在肝癌发生中的关键作用和分子机制，并为克服HCC中的索拉非尼耐药性提供了一种有前景的基于piRNA的纳米递送策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/2375c88c556d/bmr.0225.fig.010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/646566ea32e7/bmr.0225.fig.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/976456fd8b01/bmr.0225.fig.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/ae6ea374533c/bmr.0225.fig.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/fb077717c33e/bmr.0225.fig.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/e89baa4fa954/bmr.0225.fig.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/b7f31eba1b4c/bmr.0225.fig.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/bbd773aed818/bmr.0225.fig.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/b7869fc183a8/bmr.0225.fig.008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/481720d3e6be/bmr.0225.fig.009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/2375c88c556d/bmr.0225.fig.010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/646566ea32e7/bmr.0225.fig.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/976456fd8b01/bmr.0225.fig.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/ae6ea374533c/bmr.0225.fig.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/fb077717c33e/bmr.0225.fig.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/e89baa4fa954/bmr.0225.fig.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/b7f31eba1b4c/bmr.0225.fig.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/bbd773aed818/bmr.0225.fig.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/b7869fc183a8/bmr.0225.fig.008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/481720d3e6be/bmr.0225.fig.009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29c5/12218766/2375c88c556d/bmr.0225.fig.010.jpg

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本文引用的文献

[1]
Positive feedback between arginine methylation of YAP and methionine transporter SLC43A2 drives anticancer drug resistance.

Nat Commun. 2025-1-2

[2]
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Science. 2024-11-22

[3]
HMGA2 regulates GPX4 expression and ferroptosis in prostate cancer cells.

Biochem Biophys Res Commun. 2024-12-3

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Cell Death Dis. 2023-11-30

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Int J Nanomedicine. 2023

[10]
Polyphyllin I induced ferroptosis to suppress the progression of hepatocellular carcinoma through activation of the mitochondrial dysfunction via Nrf2/HO-1/GPX4 axis.

Phytomedicine. 2024-1

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