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Inoue made his fourth title defense as a unified bantamweight champion in a title unification bout with the reigning WBC champion Nonito Donaire on 7 June 2022, at the Saitama Super Arena in Saitama, Japan. Donaire was ranked No. 1 by The Ring and TBRB. The fight was for lineal championship and rematch of their 7 November 2019 title unification bout, which Inoue won by unanimous decision. Inoue opened as the favorite, with most odds-makers having him as a -400 favorite to win the rematch. The bout was broadcast by Amazon Prime Video domestically in Japan, and by ESPN in the United States. Inoue won the fight by a second-round technical knockout. After knocking Donaire down at the very end of the first round, Inoue once again staggered him with a left hook near the start of the second round, before finishing him with a flurry of punches at the 1:24-minute mark of the round. He became Japan's first-ever three-belt titleholder in boxing history. Inoue expressed his desire to fight the WBO champion Paul Butler in his post-fight interview, stating: “My aim is to be the undisputed champion. But if I can't, I am capable of [moving up] and fighting for a belt“. He was briefly ranked as the number one pound for pound boxer by The Ring after this victory, thus becoming the first Japanese boxer to reach that milestone
