Advances in biological regulationNov 20, 2025

Using mass spectrometry to study how cells manage stress and maintain protein balance

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 28, 2026

Abstract

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) enables comprehensive profiling of the unfolded protein response (UPR) signaling pathways.

The unfolded protein response is crucial for maintaining cellular health during endoplasmic reticulum stress.
UPR consists of three main signaling branches: ATF6, IRE1, and PERK, each with distinct and overlapping functions.
Dysregulation of UPR pathways is linked to various diseases, including cancer and age-related decline in proteostasis.
Traditional methods like transcriptomics provide limited insights into UPR regulation at the protein level.
Recent advancements in proteomics enhance the detection and analysis of low-abundance UPR proteins.
Integrating proteomics with other datasets may reveal specific molecular signatures associated with UPR activity in different conditions.

Simplified

The unfolded protein response (UPR) is a central regulator of proteostasis, coordinating cellular adaptation to endoplasmic reticulum (ER) stress. It is comprised of three signaling branches: ATF6 (activating transcription factor 6), IRE1 (inositol-requiring enzyme 1), and PERK (protein kinase RNA-like ER kinase), which mediate transcriptional and translational reprogramming of the proteostasis network. These pathways display both functional redundancy and branch-specific activities. Dysregulated UPR signaling contributes to diverse pathologies: in cancer, UPR activation supports uncontrolled proliferation and treatment resistance, whereas in aging, proteostasis decline and diminished UPR responsiveness are hallmarks. Traditional approaches, including transcriptomics and western blotting, have been widely used to monitor UPR activity, but they offer limited insight into its regulation at the protein level. In contrast, liquid chromatography-tandem mass spectrometry (LC-MS/MS) based proteomics allows comprehensive, branch-specific profiling of UPR signaling. Recent advances, including data-independent acquisition (DIA) MS and automated sample preparation, have further improved sensitivity, reproducibility, and detection of low-abundance UPR target proteins. Proteomics thus provides a systematic and scalable framework to interrogate UPR regulation across cell types and disease models. When integrated with complementary datasets, protein-level measurements can uncover context-dependent molecular signatures of UPR activity, offering insights into disease mechanisms and guiding the rational design of targeted pharmacological interventions. Future work integrating high-resolution LC-MS/MS proteomics with tissue and single-cell analyses will further clarify the role of the UPR in health and disease.

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Using mass spectrometry to study how cells manage stress and maintain protein balance

Abstract

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