I’m not sure what you’re saying here. It’s not that the feds must somehow regulate interstate commerce, it’s that the states can’t. The 21st carves out an exception.
I may be wrong, but I think it depends on whether it actually conflicts with any federal law. States can pass laws that affect interstate commerce if there's no superceding federal law and if they don't fall afoul of the Dormant Commerce Clause, which sort of generically restricts interstate protectionism.
Interstate commerce being a federal power under the Constitution prohibits states acting to regulate interstate commerce where the federal government has acted, without the permission of Congress, and prohibits the States from discriminating against out-of-state commerce generally. That doesn't mean that all State regulation of interstate commerce is prohibited, but the State's power is sharply circumscribed by the mere designation of the federal power as well as by federal action exercising that power.
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