Subamnex Ameliorates Hypoxia-Induced Pulmonary Arterial Hypertension through Modulation of the STAT3/p-STAT3 Pathway

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by progressive vascular remodeling and elevated pulmonary pressure, leading to right heart failure and high mortality, against which current treatments are limited and mechanisms remain incompletely understood. In this medicinal chemistry study, we designed, synthesized, and evaluated nine naphthalimide-polyamine derivatives (<b>7a</b>-<b>7c</b>, <b>12a</b>-<b>12b</b>, <b>17a</b>-<b>17c</b> and Subamnex) by taking advantage of the unique chemical structure and potential biological activity of polyamine derivatives. Our results demonstrate that the symmetrical polyamine azo-naphthalimide naphthalimide-polyamine derivatives, named Subamnex, suppresses pathological pulmonary arterial smooth muscle cells (PASMCs) proliferation and migration by targeting IL-6-induced STAT3 phosphorylation. By regulating key downstream effectors including NEAT1, Pim-1, and the Bax/Bcl-2 balance to attenuate remodeling, our work proposes a novel strategy to reverse vascular remodeling beyond symptom alleviation.