LCN2-mediated ferroptosis resistance in tissue homeostasis and early-stage tumorigenesis of the fallopian tube epithelium

Keiyo Imaeda; Tomohiro Tamura; Shimpei Nagai; Eiji Sugihara; Juntaro Yamasaki; Yuji Otsuki; Kohei Nakamura; Takashi Takeda; Kanako Nakamura; Yuya Nogami; Kosuke Tsuji; Tatsuyuki Chiyoda; Iori Kisu; Yusuke Kobayashi; Kouji Banno; Rui Yamaguchi; Kazuhiro Sakurada; Hideyuki Saya; Daisuke Aoki; Ahmed Ashour Ahmed; Osamu Nagano; Kenta Masuda; Wataru Yamagami

doi:10.1016/j.isci.2025.112654

LCN2-mediated ferroptosis resistance in tissue homeostasis and early-stage tumorigenesis of the fallopian tube epithelium

Keiyo Imaeda, Tomohiro Tamura, Shimpei Nagai, Eiji Sugihara, Juntaro Yamasaki, Yuji Otsuki, Kohei Nakamura, Takashi Takeda, Kanako Nakamura, Yuya Nogami, Kosuke Tsuji, Tatsuyuki Chiyoda, Iori Kisu, Yusuke Kobayashi, Kouji Banno, Rui Yamaguchi, Kazuhiro Sakurada, Hideyuki Saya, Daisuke Aoki, Ahmed Ashour AhmedOsamu Nagano, Kenta Masuda, Wataru Yamagami

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Abstract

While the fallopian tube epithelium (FTE) is known to be composed of various differentiated cells such as secretory and ciliated cells, the upstream regulatory mechanisms of cell differentiation that are essential for tissue homeostasis remain under investigation. In this study, we established human FTE organoids and identified quiescent cells within the early organoid formation by observing cellular proliferation heterogeneity. We also analyzed two single-cell transcriptomic data to trace the differentiation trajectory in human FTE, and found that the gene LCN2 serves as a marker gene of early stage of the trajectory. Genetically manipulated FTE organoids indicated that LCN2 inhibits ferroptosis and promotes cell survival under oxidative stress. In addition, the FTE organoids introduced p53 dysfunction, the common genetic characteristics of high-grade serous carcinoma, showed upregulated LCN2 expression and enhanced ferroptosis resistance. This study provides insights into the LCN2-mediated protective mechanism of human FTE quiescent cells and its potential role in tumorigenesis.

Original language	English
Article number	112654
Journal	iScience
Volume	28
Issue number	6
DOIs	https://doi.org/10.1016/j.isci.2025.112654
Publication status	Published - 20-06-2025

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Imaeda, K., Tamura, T., Nagai, S., Sugihara, E., Yamasaki, J., Otsuki, Y., Nakamura, K., Takeda, T., Nakamura, K., Nogami, Y., Tsuji, K., Chiyoda, T., Kisu, I., Kobayashi, Y., Banno, K., Yamaguchi, R., Sakurada, K., Saya, H., Aoki, D., ... Yamagami, W. (2025). LCN2-mediated ferroptosis resistance in tissue homeostasis and early-stage tumorigenesis of the fallopian tube epithelium. iScience, 28(6), Article 112654. https://doi.org/10.1016/j.isci.2025.112654

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title = "LCN2-mediated ferroptosis resistance in tissue homeostasis and early-stage tumorigenesis of the fallopian tube epithelium",

abstract = "While the fallopian tube epithelium (FTE) is known to be composed of various differentiated cells such as secretory and ciliated cells, the upstream regulatory mechanisms of cell differentiation that are essential for tissue homeostasis remain under investigation. In this study, we established human FTE organoids and identified quiescent cells within the early organoid formation by observing cellular proliferation heterogeneity. We also analyzed two single-cell transcriptomic data to trace the differentiation trajectory in human FTE, and found that the gene LCN2 serves as a marker gene of early stage of the trajectory. Genetically manipulated FTE organoids indicated that LCN2 inhibits ferroptosis and promotes cell survival under oxidative stress. In addition, the FTE organoids introduced p53 dysfunction, the common genetic characteristics of high-grade serous carcinoma, showed upregulated LCN2 expression and enhanced ferroptosis resistance. This study provides insights into the LCN2-mediated protective mechanism of human FTE quiescent cells and its potential role in tumorigenesis.",

keywords = "Cell biology, Omics, Tissue Engineering",

author = "Keiyo Imaeda and Tomohiro Tamura and Shimpei Nagai and Eiji Sugihara and Juntaro Yamasaki and Yuji Otsuki and Kohei Nakamura and Takashi Takeda and Kanako Nakamura and Yuya Nogami and Kosuke Tsuji and Tatsuyuki Chiyoda and Iori Kisu and Yusuke Kobayashi and Kouji Banno and Rui Yamaguchi and Kazuhiro Sakurada and Hideyuki Saya and Daisuke Aoki and Ahmed, {Ahmed Ashour} and Osamu Nagano and Kenta Masuda and Wataru Yamagami",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = jun,

day = "20",

doi = "10.1016/j.isci.2025.112654",

language = "English",

volume = "28",

journal = "iScience",

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Imaeda, K, Tamura, T, Nagai, S, Sugihara, E, Yamasaki, J, Otsuki, Y, Nakamura, K, Takeda, T, Nakamura, K, Nogami, Y, Tsuji, K, Chiyoda, T, Kisu, I, Kobayashi, Y, Banno, K, Yamaguchi, R, Sakurada, K, Saya, H, Aoki, D, Ahmed, AA, Nagano, O, Masuda, K & Yamagami, W 2025, 'LCN2-mediated ferroptosis resistance in tissue homeostasis and early-stage tumorigenesis of the fallopian tube epithelium', iScience, vol. 28, no. 6, 112654. https://doi.org/10.1016/j.isci.2025.112654

TY - JOUR

T1 - LCN2-mediated ferroptosis resistance in tissue homeostasis and early-stage tumorigenesis of the fallopian tube epithelium

AU - Imaeda, Keiyo

AU - Tamura, Tomohiro

AU - Nagai, Shimpei

AU - Sugihara, Eiji

AU - Yamasaki, Juntaro

AU - Otsuki, Yuji

AU - Nakamura, Kohei

AU - Takeda, Takashi

AU - Nakamura, Kanako

AU - Nogami, Yuya

AU - Tsuji, Kosuke

AU - Chiyoda, Tatsuyuki

AU - Kisu, Iori

AU - Kobayashi, Yusuke

AU - Banno, Kouji

AU - Yamaguchi, Rui

AU - Sakurada, Kazuhiro

AU - Saya, Hideyuki

AU - Aoki, Daisuke

AU - Ahmed, Ahmed Ashour

AU - Nagano, Osamu

AU - Masuda, Kenta

AU - Yamagami, Wataru

PY - 2025/6/20

Y1 - 2025/6/20

N2 - While the fallopian tube epithelium (FTE) is known to be composed of various differentiated cells such as secretory and ciliated cells, the upstream regulatory mechanisms of cell differentiation that are essential for tissue homeostasis remain under investigation. In this study, we established human FTE organoids and identified quiescent cells within the early organoid formation by observing cellular proliferation heterogeneity. We also analyzed two single-cell transcriptomic data to trace the differentiation trajectory in human FTE, and found that the gene LCN2 serves as a marker gene of early stage of the trajectory. Genetically manipulated FTE organoids indicated that LCN2 inhibits ferroptosis and promotes cell survival under oxidative stress. In addition, the FTE organoids introduced p53 dysfunction, the common genetic characteristics of high-grade serous carcinoma, showed upregulated LCN2 expression and enhanced ferroptosis resistance. This study provides insights into the LCN2-mediated protective mechanism of human FTE quiescent cells and its potential role in tumorigenesis.

AB - While the fallopian tube epithelium (FTE) is known to be composed of various differentiated cells such as secretory and ciliated cells, the upstream regulatory mechanisms of cell differentiation that are essential for tissue homeostasis remain under investigation. In this study, we established human FTE organoids and identified quiescent cells within the early organoid formation by observing cellular proliferation heterogeneity. We also analyzed two single-cell transcriptomic data to trace the differentiation trajectory in human FTE, and found that the gene LCN2 serves as a marker gene of early stage of the trajectory. Genetically manipulated FTE organoids indicated that LCN2 inhibits ferroptosis and promotes cell survival under oxidative stress. In addition, the FTE organoids introduced p53 dysfunction, the common genetic characteristics of high-grade serous carcinoma, showed upregulated LCN2 expression and enhanced ferroptosis resistance. This study provides insights into the LCN2-mediated protective mechanism of human FTE quiescent cells and its potential role in tumorigenesis.

KW - Cell biology

KW - Omics

KW - Tissue Engineering

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UR - http://www.scopus.com/inward/citedby.url?scp=105005867281&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2025.112654

DO - 10.1016/j.isci.2025.112654

M3 - Article

AN - SCOPUS:105005867281

SN - 2589-0042

VL - 28

JO - iScience

JF - iScience

IS - 6

M1 - 112654

ER -

LCN2-mediated ferroptosis resistance in tissue homeostasis and early-stage tumorigenesis of the fallopian tube epithelium

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