Bernal's team-mate Ivan Ramiro Sosa took second, edging out Nans Peters who claimed the final podium place, a deserved result for his AG2R La Mondiale team.
"I'm really happy. To win is always difficult. It's my first win in Italy after a lot of races," Bernal said.
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"I was feeling really good during the race so I asked the guys to do a good tempo. Sosa did a really good job.
"I won the race but I thought he was the stronger. He showed that he is one of the strongest in the climb."
Bernal had only been ninth in the Giro dell-Emilia last weekend but will go into Saturday's Il Lombardia as one of the favourites with a strong team around him.
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Ineos set a gruelling pace up the final climb with five kilometres to go and made it difficult for any other team to take control of the race.
Mathias Frank was the first to attack but the Swiss was only able to pull out a gap of around five bike-lengths and he was quickly reeled in by the red-and-black trio at the front.
First Diego Rosa and then Sosa refused to relent from the punishing pace, reducing the leading group to just seven with three kilometres to go.
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Dan Martin had fallen earlier in the day but was able to stick with them, hanging onto the back of the two AG2R La Mondiale riders who were doing a remarkable job of sticking with the power of the Ineos front-runners.
But with two kilometres left, Sosa upped the tempo again to break the legs of the remaining followers and Bernal was launched 1,800 from the finish.
He hit the Flamme Rouge with a gap of 17 seconds and widening, showing exactly how strong he is even at this late stage in the season.
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