Python is inherently single-threaded. https://wiki.python.org/moin/GlobalInterpreterLock

It would be far easier and more effective to remove most of the transaction-handling code from p2pool, and make share objects contain only the merkle root plus the coinbase transaction (and the merkle path thereto). However, I have not had the time to do that, and nobody else seems to be interested in doing it. Even though it would be much easier, it's not super easy to do.

Note: Bitcoin Core is *also* mostly single-threaded, although not quite to the same extent as p2pool.