Background: Chronic stress-related disorders, such as cardiovascular neurosis, are frequently associated with elevated cortisol levels, which can impair mitochondrial function and contribute to cardiomyocyte injury. Fibroblast growth factor 19 (FGF19), a metabolic regulator with known cytoprotective properties, has been implicated in the maintenance of mitochondrial homeostasis. However, its role in mitigating cortisol-induced cardiac stress remains poorly understood. This study aimed to investigate whether FGF19 confers protection to cardiomyocytes against cortisol-induced mitochondrial dysfunction and apoptosis, and to elucidate the underlying molecular mechanisms.

Methods: Human AC16 cardiomyocytes were treated with cortisol and subjected to either FGF19 overexpression or knockdown. Cell viability, apoptosis, and mitochondrial function were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), adenosine triphosphate (ATP) quantification, mitochondrial DNA (mtDNA) copy number analysis, and mitochondrial membrane potential assessment using JC-1 dye, and reactive oxygen species (ROS) measurement. Western blot analysis was performed to examine the expression of proteins involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (TFAM), as well as proteins regulating mitochondrial dynamics, such as Mitofusin 1 and 2 (Mfn1/2) and dynamin-related protein 1 (Drp1).

Results: Cortisol treatment significantly downregulated FGF19 expression, impaired mitochondrial function, and increased apoptosis (p < 0.01). Overexpression of FGF19 enhanced mitochondrial biogenesis, preserved mitochondrial membrane potential, and reduced oxidative stress, thereby mitigating mitochondrial dysfunction and apoptosis (p < 0.01). Conversely, FGF19 knockdown aggravated mitochondrial damage, elevated ROS levels, further reduced cell viability, and promoted apoptosis (p < 0.01). The opposing phenotypes observed with FGF19 overexpression and silencing underscore its critical role in preserving mitochondrial integrity and promoting cell survival under cortisol-induced stress.

Conclusion: This study demonstrates that FGF19 mitigates cortisol-induced cardiomyocyte injury by improving mitochondrial function and reducing apoptosis. These findings provide experimental evidence supporting FGF19 as a potential therapeutic target for the treatment of cardiovascular neurosis and related stress-induced cardiac disorders.