Zn(II) is an essential transition metal that cofactors ~10% of the human proteome to play key roles in regulating immune function and inflammation. A large proportion of this Zn(II) proteome are Zinc Finger (ZF)-containing proteins which coordinate Zn(II) with 4 Cys/His ligands to achieve secondary structure and function. ZFs are, however, subject to adventitious metal binding and post-translational modification (PTM), both of which may affect protein structure and function. The nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway is a focal point for inflammation and immunity and is regulated by numerous ZFs. Tristetraprolin (TTP) is one such ZF that negatively regulates the NFκB pathway by degrading cytokine mRNAs. I first set out to understand TTP’s interactions with the toxic metal, lead (Pb(II)), by expressing and purifying an apo-peptide construct of TTP’s two CCCH ZF domains (TTP-2D). I utilized an array of optical spectroscopies which revealed that Pb(II) binds apo-TTP-2D with an affinity comparable to Zn(II) and perturbs TTP-2D’s structure. Furthermore, Pb2-TTP-2D had a higher affinity for a biologically relevant mRNA target, suggesting a change in protein function with the non-native metal. To elucidate ZF persulfidation, a PTM of Cys-SH to Cys-SSH, I used TTP-2D as a template for amino acid mutation and testing of various ZF domains for their reactivity with hydrogen sulfide (H2S), the endogenously produced signaling molecule associated with persulfidation. I designed a series of mutants of TTP’s first ZF domain (TTP-1D) to include all iterations of Cys ligands for binding (i.e. CHHH, CCHH, and CCCC), representing other biological ZF domains. I found that all domains reacted with H2S, showing a minimum requirement of one Cys residue for persulfidation. Finally, I am connecting ZF persulfidation with the inflammatory response of the NFκB pathway during TNFα stimulation in ongoing cell studies. To discern the requirements for H2S and persulfidation in the inflammatory response, we have validated a knockout cell line which significantly reduces persulfdation. We have prepared chemoselective proteomics samples which will identify ZF-persulfides during inflammation to compare against the resting state. Continued studies will investigate the functional impact of persulfidation on novel ZF-persulfides identified from these data.