1

I have a list with emails to exclude but my MC instance uses a unique sales cloud contact key (003) as the subscriber key.

Can I exclude these emails using EMAIL as the subscriber key?

2

You could write those emails onto an auto-suppression configuration (ASC) and assign that ASC to either your intended send classification (commercial / transactional / both) for "global" usecases, or the relevant sender profiles for "specific" usecases, and those subscribers will be automatically excluded based on their email address on that ASC.

ASCs technically are set up as sendable data extensions with Email as Subscriber Key. Subscriber Key in an ASC can be used as "decoration" but has no real effect.

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