Persona 4 deals with trans themes and handles them in a wholly insulting way. Naoto, who presents as a man for much of the game, is later revealed to have been female assigned at birth. Immediately after this revelation, the game tells the player that Naoto didn’t actually want to be a man. Naoto was just trying to escape sexism.
This is incredibly problematic, because it is the same rhetoric used by transphobic people to erase trans men. The game erases Naoto’s identity as a trans man with that rhetoric, and from that point on the game treats Naoto as a woman, complete with the cast forcing Naoto into feminine roles and insulting situations against his will. Naoto is forced into a female beauty pageant that includes a swimsuit contest. Characters get hold of his medical charts, violating his privacy in doing so. The player character can even choose to abuse Naoto’s emotional investment in the protagonist to make him act more feminine.
This is in addition to content produced after Persona 4’s original release, which regularly sexualizes Naoto as a woman.
Last, but not least, the game uses a mad scientist experiment as a metaphor for gender reassignment surgery. GRS is necessary for some trans people to feel comfortable with their bodies, and the game, in the same moment that it is erasing Naoto’s identity as a trans man, frames that operation as horrific and morally wrong.
In summary, the game erases Naoto’s trans identity, equates GRS with a mad scientist experiment, forces Naoto into more feminine roles and situations despite the fact that he is clearly uncomfortable with it, and sexualizes Naoto as a woman.
Persona 4 is transphobic in the extreme.
Addendum: Whether or not you interpret Naoto as a trans man does not change that there are majorly transphobic elements in his story, the most blatant of which is the GRS metaphor. There is also a lot of sexism in how the cast treats him after he is outed to them.