Chronic stress significantly contributes to the development of depressive disorders, with the hypothalamic–pituitary–adrenal (HPA) axis playing a central role in mediating stress responses. This review examines the neurobiological alterations in the hippocampus linked to HPA axis dysregulation in chronic stress-associated depressive disorders. The prolonged activation of the HPA axis disrupts cortisol regulation, leading to the decline of both physical and mental health. The chronic stress-induced HPA axis dysfunction interacts with inflammatory pathways and generates oxidative stress, contributing to cellular damage and neuroinflammation that further aggravates depressive symptoms. These processes result in structural and functional alterations in the hippocampus, which is essential for emotional regulation and cognitive function. Comprehending the impact of chronic stress on the HPA axis and associated neurobiological pathways is essential for formulating effective interventions for depressive disorders. This review summarises the existing findings and underscores the necessity for future investigations into intervention strategies to improve physical and psychological wellbeing targeting at HPA axis dysregulation for the betterment of psychological wellbeing and human health.

AUTHORS: Ai Ai Lei, Vanessa Wen Xian Phang, Yu Zhao Lee, Audrey Siew Foong Kow, Chau Ling Tham, Yu-Cheng Ho, and Ming Tatt Lee

SOURCE TITLE: International Journal of Molecular Sciences

VOLUME: 26 | ISSUE: 7

YEAR: 2025

ISSN OR ISBN: 1661-6596

RANK BY JOURNAL IMPACT FACTOR (JIF): Q1

DOI: https://doi.org/10.3390/ijms26072940

Date of Input: 12/11/2025 | Updated: 12/11/2025 | nadia_rahman