RORγt inhibitor(Merck)

This study aimed to investigate the therapeutic potential of myricetin, a natural flavonoid, in Alzheimer's disease (AD) by targeting Th17 cell‐mediated neuroinflammation through inhibition of the transcription factor RORγt.

Virtual screening of 47,963 compounds identified myricetin as a potential RORγt inhibitor, validated by molecular docking and dynamics simulations. In vivo, 3xTg‐AD mice were treated with myricetin (50 mg/kg/day) for 8.5 weeks, followed by behavioral tests (novel object recognition, Morris water maze) and pathological analyses (HE/Nissl staining, immunohistochemistry, Western blot). In vitro, Th17 polarization assays and mechanistic studies (ChIP, EMSA, MST) were performed to elucidate myricetin's action on RORγt‐IL‐17 signaling.

Myricetin exhibited stable binding to RORγt (Kd = 6.40 μM), suppressing Th17 polarization and IL‐17 production. In AD mice, myricetin improved cognitive function, reduced neuronal damage, decreased Aβ plaques and phosphorylated tau levels, and attenuated microglial activation. Mechanistically, myricetin blocked RORγt recruitment to the IL17 promoter, downregulating IL‐17 transcription.

Myricetin ameliorates AD pathology by inhibiting RORγt‐driven Th17 polarization, highlighting its potential as a therapeutic agent for AD.

The RORγt (nuclear receptor retinoid‐related orphan receptor γt) has been identified as a master transcription factor critical for the differentiation of T helper 17 cells, the primary source of IL‐17A (interleukin‐17A). We previously demonstrated that IL‐17A promotes neuroinflammation and sympathetic excitation, contributing to cardiac dysfunction in heart failure and angiotensin II (ANG II)‐induced hypertension. The present study sought to determine whether inhibiting RORγt, thereby reducing IL‐17A production, could attenuate microglial activation, neuroinflammation, and sympathetic excitation by preserving the integrity of the blood–brain barrier (BBB) in ANG II‐induced hypertensive rats.

Rats underwent a 2‐week subcutaneous infusion of ANG II, with concurrent daily subcutaneous administration of the RORγt inhibitor digoxin or vehicle.

Compared with controls, ANG II‐infused rats exhibited elevated IL‐17A levels in both the periphery and brain, along with increased blood pressure and sympathetic tone—effects that were significantly attenuated by inhibiting RORγt with digoxin. ANG II‐infused rats also displayed heightened BBB permeability, decreased expression of the BBB regulator Mfsd2a (major facilitator superfamily domain‐containing protein 2a), increased caveolar transcytosis, and degradation of tight junction proteins in BBB endothelial cells within the hypothalamic paraventricular nucleus, a key autonomic regulatory brain center, all of which were alleviated by digoxin. Additionally, ANG II‐infused rats showed marked microglial activation and elevated expression of proinflammatory cytokines within the paraventricular nucleus, both of which were mitigated by digoxin.

These findings suggest that RORγt inhibition reduces neuroinflammation and sympathetic activation to ameliorate ANG II‐induced hypertension, likely by mitigating IL‐17A‐induced BBB disruption and microglial activation in the paraventricular nucleus.