Wimbledon winner Rybakina out at Cincinnati
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The Kazakh, who lifted the All England Club trophy last month against the odds, exited the pre-US Open event in 92 minutes as she went down to the American titleholder from 2019.
The pair struggled through a 21-point, 12-minute opening game, with Keys then turning on her jets to win the second in seconds.
Keys also came from a break down in the second set to carve out victory.
"Elena is a remarkable player who can turn a match around at any moment," unseeded Keys said. "I needed to stay out front.
"It felt like I needed 12 match points, so I'm very happy to get the win. If you back off against her, she will run you around.
"It's never good if she is in control, I had to take advantage of any ball I could."