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The study tests whether canonical HSR pathways are universal or whether specific human cell lines show distinct transcriptional programs after heat shock and recovery. RNA sequencing across HEK293, HepG2, and HeLa identifies conserved canonical HSR activation alongside enrichment of non-canonical “Receptor Ligand Activity” signals, with cell-line-specific expression and validation by qPCR across time points. 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HSR is activated by stress such as elevated temperature and drives expression of heat shock factors and proteins that protect cells from proteotoxic stress.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How did the researchers compare responses to heat shock across cell lines?",{"text":117,"@type":113},"The study compared transcriptomic responses of HEK293, HepG2, and HeLa cells under control conditions immediately after heat shock and after an 8-hour recovery period. RNA sequencing was used to characterize pathway activation and gene expression changes.",{"name":119,"@type":110,"acceptedAnswer":120},"What non-canonical pathway was enriched and how was it validated?",{"text":121,"@type":113},"A non-canonical “Receptor Ligand Activity” pathway was enriched across all cell lines. 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Nicholls and Vladimir N. Uversky  \nReceived: 27 December 2024  \nRevised: 20 January 2025  \nAccepted: 22 January 2025  \nPublished: 26 January 2025  \nCitation: Reinschmidt, A.; Solano, L.; Chavez, Y.; Hulsy, W.D.; Nikolaidis, N. Transcriptomics Unveil Canonical and Non-Canonical Heat Shock-Induced Pathways in Human Cell Lines. Int. J.  \nMol. Sci. 2025, 26, 1057. [https://](https://)[ ](https://)[doi.org/10.3390/ijms26031057](doi.org/10.3390/ijms26031057)  \n[Copyright:](Copyright:) © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) .  \nDepartment of Biological Science, Center for Applied Biotechnology Studies, and Center for Computational and Applied Mathematics, California State University Fullerton, Fullerton, CA 92831, USA;  \n[areinschmidt4@csu.fullerton.edu](areinschmidt4@csu.fullerton.edu) (A.R.); [lesolano@uci.edu](lesolano@uci.edu) (L.S.); [yonny@csu.fullerton.edu](yonny@csu.fullerton.edu) (Y.C.);  \n[wdhulsy@csu.fullerton.edu](wdhulsy@csu.fullerton.edu) (W.D.H.)  \n* [Correspondence: nnikolaidis@fullerton.edu](Correspondence: nnikolaidis@fullerton.edu)  \n† Current address: Center for Complex Biological Systems, University of California, Irvine, CA 92697, USA.  \nAbstract: The cellular stress response (CSR) is a conserved mechanism that protects cells from-environmental and physiological stressors. The heat shock response (HSR), a critical component of the CSR, utilizes molecular chaperones to mitigate proteotoxic stress caused by elevated temperatures. We hypothesized that while the canonical HSR pathways are conserved across cell types, specific cell lines may exhibit unique transcriptional responses to heat shock. To test this, we compared the transcriptomic responses of HEK293, HepG2, and HeLa cells under control conditions immediately following heat shock and after an 8-h recovery period. RNA sequencing revealed the conserved activation of canonical HSR pathways, including the unfolded protein response, alongside the-enrichment of thenon-canonical “Receptor Ligand Activity” pathway across all cell lines. Cell-line-specific variations were observed, with HepG2 cells exhibiting significantly higher ex-pression levels of certain genes compared to other cell lines under stress conditions, as well as greater fold changes in gene expression relative to its control conditions. Validation by qPCR confirmed the activation of key genes within the “Receptor Ligand Activity” pathway across time points. These findings provide insights into conserved and context-specific aspects of the HSR, contributing to a more comprehensive understanding of stress response mechanisms across mammalian cells.  \nKeywords: heat shock response (HSR); RNA sequencing; cellular stress response (CSR)  \n1. Introduction  \nThe cellular stress response (CSR) is a critical survival mechanism that helps cells cope with environmental stressors, and the heat shock response (HSR) is one of its most essential components [1–7] . The HSR is primarily activated by temperature increases and other stressors, triggering the activation of heat shock factors (HSFs), especially HSF1, which then drive the expression of heat shock proteins (HSPs) . These molecular chaperones, including HSP70 and HSP90, facilitate protein homeostasis by refolding misfolded proteins, preventing aggregation, and modulating apoptosis [3–5,8–12] . While the canonical HSR is well-characterized, the full scope of its regulatory mechanisms and potential adaptations to different cellular contexts s","cbCaihbqRFDMo7tR","https://ap.wps.com/l/cbCaihbqRFDMo7tR","pdf",5953523,21,"English","# Introduction\n## Background: CSR and canonical HSR mechanisms\n## Cancer relevance and knowledge gaps\n## Study aim and experimental comparison","[{\"question\":\"What is the relationship between CSR and the heat shock response (HSR) in this study?\",\"answer\":\"CSR is a conserved survival mechanism, and HSR is a critical component of CSR. HSR is activated by stress such as elevated temperature and drives expression of heat shock factors and proteins that protect cells from proteotoxic stress.\"},{\"question\":\"How did the researchers compare responses to heat shock across cell lines?\",\"answer\":\"The study compared transcriptomic responses of HEK293, HepG2, and HeLa cells under control conditions immediately after heat shock and after an 8-hour recovery period. RNA sequencing was used to characterize pathway activation and gene expression changes.\"},{\"question\":\"What non-canonical pathway was enriched and how was it validated?\",\"answer\":\"A non-canonical “Receptor Ligand Activity” pathway was enriched across all cell lines. Validation by qPCR confirmed activation of key genes within this pathway across time points.\"}]","Transcriptomics Unveil Canonical and Non-Canonical Heat Shock-Induced Pathways in Human Cell Lines | PDF",53]