ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Embryonic Development
This article is part of the Research TopicAutophagy and Cellular Senescence: A Double-Edged Sword in Health and DiseaseView all articles
LPS–TLR4 Signaling Attenuates CHOP-Mediated Apoptosis under Endoplasmic Reticulum Stress Conditions during Porcine Embryonic Development
Provisionally accepted
Gyu-Hyun Lee
Cheng-Lin ZhanSong-Hee LeeQin-Yue LuYing-Yan JinJi-Yeon LeeKyung-Tae Shin
Xiang-Shun Cui*- Chungbuk National University, Cheongju, Republic of Korea
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Persistent endoplasmic reticulum (ER) stress impairs early embryonic development by inducing apoptosis through C/EBP homologous protein (CHOP). Toll-like receptor 4 (TLR4), traditionally recognized for its role in innate immunity, has recently emerged as a modulator of intracellular stress responses. Lipopolysaccharide (LPS), a natural TLR4 agonist derived from Gram-negative bacteria, elicits both pro-inflammatory and cytoprotective effects depending on the cellular context and dosage. This study aimed to elucidate the role of TLR4 signaling in the regulation of CHOP-mediated apoptosis during porcine preimplantation development under ER stress. Porcine embryos were treated with tunicamycin (TM) 5 nM to induce ER stress and co-treated with LPS 10 µM to activate TLR4 signaling. LPS treatment significantly improved blastocyst formation rates compared to TM groups (TM: 37.50 ± 4.77% vs. TM+LPS: 52.89 ± 4.86%). Consistent with this improvement, the total cell number per blastocyst was significantly restored by LPS co-treatment (Control: 55.63 ± 2.15% vs. TM: 38.61 ± 2.57%; TM + LPS: 48.84 ± 0.83%), confirming enhanced cell proliferation and developmental quality under ER stress conditions. LPS co-treatment markedly reduced CHOP protein expression and suppressed the expression of ATF4, indicating alleviation of PERK-ATF4-CHOP signaling. Additionally, autophagy and apoptosis were attenuated, as evidenced by a significantly decreased LC3-II/LC3-I ratio and a reduced number of TUNEL-positive cells. Notably, TLR4 knockdown abolished these LPS-mediated protective effects, confirming the requirement of TLR4 in mitigating ER stress-induced damage. These findings demonstrated that LPS-mediated TLR4 signaling suppressed CHOP-induced apoptosis and autophagy under persistent ER stress, thereby improving embryonic viability. This study provides novel mechanistic insights into the non-canonical role of TLR4 in early embryonic development and highlights its therapeutic potential for improving in vitro embryo culture systems.
Keywords: Apoptosis, CHOP, Endoplasmic Reticulum Stress, porcine embryonic development, TLR4
Received: 20 Nov 2025; Accepted: 03 Feb 2026.
Copyright: © 2026 Lee, Zhan, Lee, Lu, Jin, Lee, Shin and Cui. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xiang-Shun Cui
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