Which issue in human spaceflight is most pressing: radiation, psychology, management of life support resources, or muscle wastage?

Challenges to human spaceflight include the following:

I know these are all major challenges to putting boots on Mars, but which is the most important to solve before we can make the first crewed Mars mission happen?

There is no technical barrier to a Apollo style Mars mission, and has not been since Skylab/Mir, with a well math'd Venus flyby proposed for 1973 that had answers for most of the points in the question.

The issue is this mission design is very much brute force - launch a large craft and then stuff it with several years worth of food for a very small (2-3 person) crew, that crew does as little as possible while in transit (reducing life support needs). If possible provide a lander so at Mars crew can plant a flag rather than just looking from orbit, then fly home.

The most costly/risky part of this mission is the lander, which is outside the human factors scope of the question.

The issue with the above mission profile is 'why'. It achieves a very expensive 'first' but otherwise is mostly about astronauts struggling with boredom and pooping in a bag which is hard to justify to taxpayers (and probably the crew).

An obvious improvement is to make life support more closed loop:

Issue is that this makes mission much more complicated, and in particular there is three axis problem space of maximizing closed loop efficiency, reducing system mass and maximizing system reliability that while certainly solvable tends to produce decision paralysis in full system design in absence of firm mission scope and budget, while plenty of work has been done at subsystem level.

This means that should someone NEED to pull together a Mars mission 'by the end of the decade' most of the life support parts are already there, they just need to commit to choices and start iterating on hardware (ie spending money in large amounts).

So it could be argued the biggest obstacle is right combination of money and willingness to lock in a choice that is 'wrong' by at least one metric.

Spoiler: Opinion based answer

I vote for “life support” as the most pressing question since it is an absolute necessity for astronauts making the round trip alive. Closed-loop life support has not been demonstrated.

Radiation will produce an increased probability of cataracts and cancer deaths after return, but would not prevent astronauts from returning.

Muscle and bone wasting could be crippling. There is also a risk of fatality during the mission due to kidney stones from hypercalcemia secondary to bone wasting.

Psychological stress would likely be handled by those steely eyed missile men. They got the right stuff.