<p>Hypoxia-induced pulmonary hypertension (HPH), a consequence of lung pathologies, is linked to changes in immune responses and inflammation. SIRT5 is recognized as the only enzyme capable of removing succinyl groups. The focus of this research was to explore the involvement of SIRT5 in HPH and to elucidate the associated mechanisms. Models simulating HPH were created in both living organisms and controlled laboratory settings under conditions of low oxygen. To investigate autophagy, transmission electron microscopy (TEM) was employed for ultrastructural analysis, while reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to measure the expression of autophagy-related genes. Cell viability was determined using the cell counting kit-8 (CCK-8) assay. The concentrations of inflammatory cytokines were quantified using ELISA, and flow cytometry was applied to evaluate reactive oxygen species (ROS) levels. To explore the interaction between PDK1 and SIRT5, co-immunoprecipitation (Co-IP) followed by Western blot analysis was conducted. Findings revealed that low oxygen conditions prompted mitophagy and elevated levels of both mRNA and proteins associated with this process in experiments conducted in organisms as well as in cellular models.&#xa0;Under conditions of low oxygen, the expression of SIRT5 was found to be reduced. Hypoxia enhanced cell viability, ROS level, angiogenesis-related protein levels, and inflammatory cytokine levels in pulmonary microvascular endothelial cells (PMVECs), effects that were reversed upon SIRT5 overexpression. Mechanistically, SIRT5 interacted with PDK1, desuccinylating PDK1 and thereby inhibiting mitophagy and inflammation associated with HPH. In conclusion, SIRT5 inhibited mitophagy and inflammation in HPH by regulating the desuccinylation of PDK1, potentially offering effective therapeutic strategies for treating HPH.</p>