Assuming I understand the problem correctly, you just need to convert your hashtable values to regexp patterns that match any of the variables, then do a substitution. Something like:

sub replace {
    my ($line, $nodes, $suffix) = @_;
    (my $matchNodes = $nodes) =~ s/,/|/g;
    $line =~ s/\b($matchNodes):./$1:$suffix/g;
    return $line;
}

$line = replace($line, $runset{'POWER-NODE'}, 'P');
$line = replace($line, $runset{'GROUND-NODE'}, 'G');
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That assumes that there's always a single character after the colon.

Notice the \b -- that prevents it from replacing eg 'xvdd' when your runset contains 'vdd'.