# The Role of Crosstalk Between the Unfolded Protein Response and Autophagy in Diseases Associated with Sympathetic Nervous System Imbalance: Mechanisms and Therapeutic Perspectives

## TL;DR

This review explores how imbalances in the sympathetic nervous system lead to diseases by disrupting protein and autophagy processes, and suggests potential therapies.

## Contribution

The paper systematically connects SNS overactivation with UPR–autophagy dysregulation in both central and peripheral tissues.

## Key findings

- Chronic SNS overactivation causes metabolic overload and disrupts the UPR–autophagy network.
- Central ERS or autophagy dysfunction worsens sympathetic overexcitation and disease progression.
- Targeting UPR modulators and nanomedicine offers therapeutic potential for these diseases.

## Abstract

Sympathetic nervous system (SNS) imbalance is a common pathological basis for cardiovascular diseases, non-alcoholic fatty liver disease, and diabetes. This review focuses on these diseases, analyzing two core mechanisms: excessive sympathetic excitation induced by endoplasmic reticulum stress (ERS) or autophagy dysfunction in key central nuclei (e.g., hypothalamus, rostral ventrolateral medulla); and ERS/autophagy abnormalities in peripheral target organs caused by chronic SNS overactivation. Existing studies confirm that chronic SNS overactivation promotes peripheral metabolic overload via sustained catecholamine release, inducing persistent ERS and disrupting the protective unfolded protein response (UPR)–autophagy network, ultimately leading to cell apoptosis, inflammation, and fibrosis. Notably, central ERS or autophagy dysfunction further perturbs autonomic homeostasis, exacerbating sympathetic overexcitation. This review systematically elaborates on SNS overactivation as a critical bridge mediating UPR–autophagy network dysregulation in central and peripheral tissues, and explores therapeutic prospects of targeting key nodes (e.g., chemical chaperones, specific UPR modulators, nanomedicine), providing a theoretical basis for basic research and clinical translation.