How does it work in practice, though? For example, create-react-app in NPM has a bajillion deps. Do I trust 8,000 keys? Which ones are OK?

I get that you could in principle namespace things (at least for package managers that support this) and insist on a small set of company-internal signing keys for those namespaces. But managing all that isn't easy and what about for package ecosystems that don't really have namespaces (e.g. PyPI, NuGet)?