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Actually, his tragic downfall began when he murdered Duncan.
In Act IV, scene 1, he consults with the witches who have been instructed by Hecate to mislead him because he interfered with the predictions by killing Banquo and attempting to kill Fleance. This they do by filling him with over-confidence.
In Act IV, scene 2, since he cannot get Macduff, he trys to neutralize him by killing his wife and children. This action is perhaps the most heinous of all.
Act IV, scene 3, seems to seal Macbeth's fate when Macduff goes to Malcolm and offers his services. With the help of the English king, Malcolm is able to raise an army and invade Scotland to take his rightful place as king.
All these actions lead to Macbeth's eventual downfall.
Specifically, in Act 4, Macbeth ENSURES his tragic downfall when he kills the wife and children of Macduff.
There are other keys to his downfall previously, but this is specific to Act 4.
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