Don't have Him--or at least not the way he was
I never noticed this as a kid or saw it like that, but I've seen people, over the years, point out that Him has stereotypical gay-male qualities (I thought he was just vain) and having him be the main villain is homophobic, especially when all the other characters are straight. In Powerpuff Girls Z, this seemed a little less present to me--he was more like an evil clown, but, regardless, Him was disturbing to me as a child.
I understood Him was the devil or close to it and I hated feeling so uncomfortable when an episode with Him aired. I didn't like it in Powerpuff Girls Z either and I think today's kids should be spared that.
Also, to make up for the homophobia in the old series and even in Powerpuff Girls Z, why don't they have some strong gay, lesbian, and bi (since talking about bisexuality stops people from committing bi erasure) characters (also, having them be races other than white would be great)?
I could honestly see the professor being bi (as he did date Miss Keane and he just seemed to have this personality of being able to feel accepted and yet unaccepted in society) and the narrator be bi (just because he was so friendly and happy, but yet at a distance from everyone almost as if he felt he could only observe happiness, like he fit in as if he could pas for what was demanded of him, but not join in first hand). Maybe, the narrator could come in sometimes as a drawn in character and have a romance with the professor. It would be cute to see him lovingly narrate about the professor and his new step-daughters.
So, yeah, the ultimate villain should not be gay or the only gay or bi character or gay or bi, in this day and age (homophobia and biphobia still run rampant).