I think the best way to enable Inline::C using #line directives would be to implement an xsubpp (== ExtUtils::ParseXS) option to NOT generate #line directives. That shouldn't be hard.

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Oops! Turns out that's already done! Check out the linenumbers option. I haven't tested it, though.

This being said, I believe Inline::C is a deployment nightmare and should be avoided outside experiments accordingly.

Once you learned the C and perlapi stuff to write Inline::C, XS is child's play.