Although SACs exhibit attractive properties for catalysis, unraveling the catalytic mechanisms of SACs through experimental means faces significant challenges. The synthesis of SACs under harsh pyrolysis conditions results in a distribution of active sites and significant variation of the local coordination environment , posing fundamental challenges for most characterization techniques, even for the highest-resolution spectroscopic techniques . Similar to biological enzymes or transition metal complexes (TMCs), the spin state and oxidation state significantly influence the reactivity of SACs , making it challenging to assess reactivity trends due to the difficulty of experiments that precisely identify the oxidation/spin states during catalysis . To overcome these limits, first-principles modeling with density functional theory (DFT) has been a powerful tool for designing new SACs and obtaining mechanistic insights into their catalytic activities with atomic precision. These DFT simulations have revealed that both the support and coordination environment of SACs are essential in determining their catalytic reactivity, consistent with the conclusions drawn from experimental characterization . Thus, gaining a comprehensive understanding of the correlation between the structure and catalytic performance holds the key to achieving the rational design of SACs for targeted reactions at the atomic scale. Additionally, high-throughput virtual screening (HTVS) facilitates evaluation of an extensive library of catalyst candidates and the identification of promising ones. These approaches can be leveraged to elucidate the structure-reactivity relationships of SACs and to investigate the role of structural change in catalytic reactions.