Our recent work published in Journal of Medicinal Chemistry reports the discovery of novel isoxazole‑based small‑molecule antagonists of Toll‑like receptor 8 (TLR8) (https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c03148). Through medicinal chemistry optimization of an initial hit scaffold, a focused series of isoxazole derivatives was synthesized and evaluated, leading to potent inhibitors of TLR8 signaling. Structure–activity relationship analysis provided insights into the molecular determinants of receptor antagonism and highlights isoxazole scaffolds as promising starting points for the development of small‑molecule modulators of innate immune signaling.