The 222s are way too expensive to run as a replacement for the GWR castle sets or the Scotrail HSTs, even if they're made to be standard only or include downrated engines. the MPG is too high and the seating density is too low for this. More 158s would be perfect for GWR and hopefully in Scotland we'll see other types of fuel to replace 158/170s on various routes that cascade to replace the HSTs. As pure speculation, I'd extend electrification to Tweedbank to begin with
Back on topic, I would definitely put CAF Civitys with gangway connections on the Liverpool to Nottingham route, and a large fleet of them would make them perfect for the rest of the network. Either that or 172/3s which I think I mentioned before
I find it a little hard to believe that a 22x would have a significantly higher fuel use than a HST derived unit. However even then some of that cost increase would be offset by the lower track access charges from not having two fairly costly locos (yes cheap for locos, but still quite a cost given there's two of them).
As for seating, without making any changes other than rejoicing first class a standard only 22x with 5 coaches would have 275 seats, compared to the 4 coach units (303 seats) that's not going to be too many less. If that wasn't enough there's always the option to go to a 6 coach 22x which would still be the same length as the 4 coach sets, but we have seating for 340 in standard only configuration.
Whilst not ideal, of it's the choice betweena 22x or not having enough rolling stock to run the services (which unless we start buying bimodal units and/or getting a lot more electrification) could be a real possibility in (say) 10 years time (the 158's would be over 40 by then).