The government may use as wide of an interpretation of commerce as they can get away with. We've seen this happen before [0]. Sure, Let's Encrypt isn't taking money from the entities they offer certificates to. But the OFAC desk jockey assigned to that case only has to concoct some sufficiently plausible-sounding trail of money connecting the backing 501(c)3 and a sanctioned entity in order to levy penalties, and the legal team will not like that risk, even if it's unlikely for OFAC to win on appeal in a court.
This is true, of course, and I understand why some companies don't want to take the risk. But I would hope that Let's Encrypt would take the opposite stance. They were born out of the EFF and have EFF & ACLU board members! These orgs live for this type of legal fight.
IANAL, but it seems like the argument from Wickard v Filburn would apply to LE. They may not be taking money but they do impact the commerce of the market for certificates.
I disagree with that ruling, and I have some serious problems with sanctions against entire countries/regions, but it definitely makes sense that LE would interpret it as being impacted by OFAC.