Endoplasmic reticulum stress-based ATF6 signaling pathway: evaluation of 4-PBA improving retinal state in myopic guinea pigs

PURPOSE. This study aims to evaluate whether 4-phenylbutyric acid (4-PBA) ameliorates retinal damage in myopic Cavia porcellus by inhibiting endoplasmic reticulum stress (ERS)-mediated activating transcription factor 6 (ATF6) signaling pathway activation and suppressing downstream apoptotic cascades. METHODS. Lens-induced myopia (LIM) was established in Cavia porcellus with a -6.0 D lens placed on the right eye. Animals were divided into six groups: normal control (NC), LIM, LIM+SHMA (vehicle), and LIM + 4-PBA (low/medium/high doses: 60/120/240 mg/kg). Interventions lasted 4–6 weeks. Ocular parameters (refractive error, axial length) and retinal thickness (SD-OCT) were measured. Retinal function was assessed via flash electroretinography (FERG). Molecular mechanisms were analyzed through: qPCR/Western blot for ATF6/glucose-regulated protein 78 (GRP78)/C/EBP homologous protein (CHOP)/Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) expression; Immunofluorescence and co-immunoprecipitation (Co-IP) of ATF6-GRP78 interactions; Flow cytometry for apoptosis; Annexin V/PI), ROS, and mitochondrial membrane potential (JC-1); Calcium flux dynamics (non-invasive micro-test technology); Molecular docking of 4-PBA with ATF6/GRP78. RESULTS. LIM groups exhibited significant axial elongation and myopic refraction vs. NC ( P  < 0.05). 4-PBA remarkably attenuated axial elongation, accompanied by a dose-dependent manner ( P  < 0.001). Retinas in the LIM group showed thinning, disorganized layers, and reduced FERG amplitudes (Cone-b/Rod-b/OPs). By contrast, 4-PBA restored thickness and electrophysiological responses. ATF6, GRP78, and CHOP expression as well as calcium flux increased in LIM retinas, whereas 4-PBA suppressed these trends at a dose-dependent manner. Additionally, elevated ROS, mitochondrial dysfunction, Bax upregulation, Bcl-2 downregulation, and increased apoptosis occurred in the LIM Cavia porcellus. Nevertheless, 4-PBA treatment could effectively improve these effects. CONCLUSIONS. 4-PBA mitigates retinal damage in myopia by inhibiting ATF6-mediated ERS, reducing calcium overload, restoring mitochondrial function, and suppressing the ATF6-CHOP-Bax apoptotic cascade. This study identifies the ATF6 pathway as a therapeutic target for myopic retinopathy and supports 4-PBA’s potential as a retinal protective agent.