Towards site-specific manipulation in cysteine-mediated redox signaling.

Cysteine sulfenic acid (SOH) modifications are pivotal in redox signaling, yet establishing their causal biological roles remains challenging due to methodological limitations. Traditional approaches often lack precision or disrupt non-redox cysteine functions. This perspective highlights two innovative chemical biology strategies to address these challenges: (1) integrating bioorthogonal cleavage chemistry with genetic code expansion for site-specific SOH incorporation in proteins of interest, enabling controlled activation of redox events, and (2) developing redox-targeted covalent inhibitors (TCIs) to selectively block SOH modifications. By bridging technological innovation with mechanistic inquiry, these strategies not only help elucidate SOH-mediated signaling networks for a better understanding of redox biology, but also hold therapeutic promise for precise redox medicine.