SMAD3 and heart failure: The first-line drug sacubitril/valsartan demonstrates this principle by enhancing natriuretic peptides (cGMP/PKG-mediated Smad3 inhibition) while suppressing angiotensin II (NF-κB activation), it concurrently targets fibrotic and inflammatory axes.[121] Similarly, QLQXC’s clinical success in the QUEST trial[112] likely stems from its multihub regulation, reducing miR-34a overexpression while normalizing TGF-β/NF-κB crosstalk in heart failure with reduced ejection fraction patients.