A　model　coupling　first　principles　and　thermodynamics　was　developed　to　describe　the　thermal　stability　of　a　nanograin　structure　in　solid　solution　alloys.　The　thermodynamic　functions　of　solute　segregation　and　conditions　for　thermal　stabilization　were　demonstrated　for　both　strongly　and　weakly　solute-segregating　systems.　The　dependence　of　segregation　behavior　on　the　grain　size,　solute　concentration　and　temperature　was　quantified,　where　the　parameters　to　control　destabilization　of　the　nanograin　structure　at　a　given　temperature　were　predicted.　For　the　first　time　it　was　found　that　there　exists　a　transformation　from　the　single-extreme　to　dual-extreme　rule　of　the　total　Gibbs　free　energies　of　the　solid　solution　systems　with　the　decrease　of　solute　concentration　or　increase　of　temperature.　The　model　calculations　were　confirmed　quantitatively　by　the　experimental　results,　and　a　nanocrystalline　W-10　at%Sc　solid　solution　with　a　highly　stable　grain　structure　in　a　broad　range　from　room　temperature　to　1600　K　was　prepared.　The　universal　mechanism　disclosed　in　this　study　will　facilitate　the　design　of　nanocrystalline　alloys　with　high　thermal　stability　through　matching　of　the　doping　element　and　the　initial　grain　size.