Nitrite-producing　denitrification　granular　sludge　(NPG)　is　emerging　as　a　novel　approach　to　employing　anammox　for　cost-efficient　nitrogen　removal　from　high-strength　nitrate-containing　wastewater.　However,　the　underlying　impact　of　increasing　stress　of　nitrite　(NO2–-N)　accumulation　on　microbial　metabolism　and　cooperation　of　denitrifying　bacteria　and　heterotrophs　in　NPG　was　still　not　clear.　This　study　first　demonstrated　a　high-rate　NPG　system　with　elevating　nitrate　(NO3–-N)　from　52.4　mg/L　to　613.2　mg/L.　During　this　operation,　a　rapid　increase　in　granular　size　from　322.8　µm　to　1124.0　µm　was　observed　with　a　relatively　stable　nitrate-to-nitrite　transformation　ratio　(NTR)　as　high　as　83.0　%,　and　effluent　NO2–-N　of　increasing　from　16.5　mg/L　to　331.9　mg/L.　Such　an　increasing　NO2–-N　stress　improved　the　capability　of　the　TCA　cycle　with　rising　intermediates　of　amino　acid　metabolism.　This　further　stimulated　the　production　of　exocellular　organic　matter　that　replenished　as　electron　donors　and　promoted　the　growth　of　granular　size.　The　homogeneously　spatial　distribution　of　key　bacteria　(Thauera)　surrounding　the　NPG　with　a　calcium-dominated　inorganic　core　inside　was　revealed　to　play　a　key　role　in　enhanced　substrate　transfer　capability.　Genes　nar　and　nap　encoding　NO3–-N　reductase　dominated　by　key　species　belonging　to　Thauera　showed　much　higher　abundance　than　that　encoding　NO2–-N　reductase,　which　was　the　key　reason　for　relatively　stable　NO2–-N　accumulation.　It　illustrated　the　excellent　persistence　of　NPG　to　high　NO2–-N　stress　with　special　structure　of　functional　bacteria　inside　granules,　providing　a　great　potential　for　the　treatment　of　high-strength　nitrate-containing　wastewater.　©　2023　Elsevier　B.V.