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It's not necessary to use Cloudflare hosted DNS to use R2 with a custom subdomain.

Make a CNAME record the same way you would for a CDN subdomain.

(I am not yet running this in production, YMMV.)

Then you don't get edge cache though, right? And maybe some other features?

The benefit of not being MITM'd by Cloudflare is probably worth it in many cases.