VSMC-derived 3HAA activates AhR to drive abdominal aortic aneurysm formation via the p62-Nrf2 axis

Abdominal aortic aneurysm (AAA) remains a life-threatening vascular disease without effective pharmacologic therapy. Although 3-hydroxyanthranilic acid (3HAA), a kynurenine-pathway metabolite with dual redox effects, has been implicated in vascular diseases. How 3HAA instigates AAA is poorly defined.

We combined human AAA tissues, genetically modified mice, pharmacologic kynurenine-pathway inhibition, and mechanistic vascular smooth muscle cell (VSMC) studies to define 3HAA-AhR signaling in aneurysm formation.

In angiotensin (Ang) II-infused apoE^-/- mice, plasma 3HAA positively correlated with abdominal aortic expansion. Among three kynurenine pathway (KP) inhibitors, both the Kynu inhibitor (OMBA) and KMO inhibitor (NBA) significantly reduced AAA incidence, aortic diameter, and aortic weight. In Kynu^flox/floxsmMHC^{Cre +} mice, VSMC-specific Kynu deletion lowered AAA incidence and suppressed aortic remodeling, establishing a causal role for VSMC-derived 3HAA in AAA. Complementing this, AhR-deficient LdlR^-/--AhR^-/- mice were resistant to AngII-induced AAA and exhibited reduced MMP2 expression along with suppressed NF-κB p65 phosphorylation, confirming AhR's requirement for 3HAA-mediated MMP2 induction. The human AAA samples showed a stronger upregulation of AhR protein than non-aneurysmal aortic samples. Mechanistically, 3HAA disrupted autophagic flux by blocking p62-dependent Nrf2 stabilization, leading to impaired antioxidant responses, mitochondrial dysfunction, and heightened VSMC susceptibility to oxidative injury. Restoring p62 or activating Nrf2 rescued 3HAA-induced mitochondrial defects and prevented VSMC degeneration.

We conclude that 3HAA promotes AAA formation by activating AhR and suppressing p62-Nrf2-mediated mitochondrial homeostasis and targeting the kynurenine-AhR axis may offer new therapeutic strategies for treating AAA.