# LKB1–AMPK Signaling Pathway in Cardiovascular and Other Diseases

## TL;DR

The LKB1–AMPK pathway regulates energy balance and is linked to many diseases, including heart, metabolic, neurological, and cancer conditions.

## Contribution

This review systematically explores the LKB1–AMPK pathway's role in multiple diseases and highlights emerging therapeutic strategies.

## Key findings

- Dysfunction of the LKB1–AMPK pathway contributes to cardiovascular and metabolic diseases.
- LKB1 mutations drive tumorigenesis and affect cancer treatment responses.
- AMPK activators and gene therapies show promise but face challenges like tissue specificity.

## Abstract

The LKB1–AMPK signaling pathway is a master regulator of cellular energy homeostasis and a central hub in stress adaptation. As a conserved metabolic sensor, this pathway coordinates glucose, lipid, and protein metabolism, thereby sustaining physiological function across diverse tissues. Beyond its canonical role in energy balance, growing evidence highlights its dysregulation in multiple pathological conditions. Despite extensive mechanistic studies, the disease‐specific regulation and translational potential of the LKB1–AMPK pathway remain incompletely understood. This review systematically studies the molecular basis and regulatory mechanisms of LKB1–AMPK signaling in cardiovascular diseases—including atrial fibrillation, ventricular fibrillation, myocardial infarction, cardiac hypertrophy, heart failure, and atherosclerosis—where impaired pathway activity underlies energy deficits, fibrosis, oxidative stress, and arrhythmogenesis. We further explore its involvement in metabolic disorders such as diabetes and diabetic nephropathy, in neurodegenerative diseases like Alzheimer's and Parkinson's disease, and in oncology, where LKB1 mutations drive tumorigenesis and alter therapeutic responses. Emerging strategies, including metformin, novel AMPK activators, and LKB1‐based gene therapies, are highlighted as promising yet challenged by tissue specificity, off‐target effects, and genetic variation. By integrating insights from cardiovascular, metabolic, neurological, and oncological research, this review underscores the pathway's potential as both a biomarker source and therapeutic target, providing a foundation for precision medicine in complex diseases.

The LKB1–AMPK pathway has a central regulatory role in various diseases. Dysfunction of this pathway can lead to pathological processes in cardiovascular diseases (atrial fibrillation, myocardial infarction, myocardial hypertrophy, atherosclerosis), metabolic diseases (diabetes and kidney disease), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), and tumors (LKB1 mutation‐driven metabolic reprogramming).